Conveniently implantable sustained release drug compositions

ABSTRACT

This invention provides for biocompatible and biodegradable syringeable liquid, implantable solid, and injectable gel pharmaceutical formulations useful for the treatment of systemic and local disease states.

RELATED APPLICATIONS

This application is related to and claims the benefit under 35 U.S.C. §119(e) of U.S. Patent Application Ser. No. 60/831,991, filed Jul. 19,2006, and is a continuation-in-part and claims the benefit under 35U.S.C. § 120 of U.S. patent application Ser. No. 11/236,426, filed Sep.27, 2005, which is related to and claims the benefit under 35 U.S.C. §119(e) of U.S. Patent Applications Ser. No. 60/709,665, filed Aug. 19,2005, and Ser. No. 60/614,484, filed Oct. 1, 2004, each entitledConveniently Implantable Sustained Release Drug Compositions, by VernonG. Wong and Louis L. Wood. Each of the foregoing applications isincorporated in its entirety herein.

FIELD OF THE INVENTION

This invention provides for biocompatible and biodegradable syringeableliquid, implantable solid, and injectable gel pharmaceuticalformulations useful for the treatment of systemic and local diseases.

BACKGROUND OF THE INVENTION

Present modes of drug delivery such as topical application, oraldelivery, and intramuscular, intravenous and subcutaneous injection mayresult in high and low blood concentrations and/or shortened half-lifein the blood. In some cases, achieving therapeutic efficacy with thesestandard administrations requires large doses of medications that mayresult in toxic side effects. The technologies relating to controlleddrug release have been attempted in an effort to circumvent some of thepitfalls of conventional therapy. Their aims are to deliver medicationson a continuous and sustained manner. Additionally, local control drugrelease applications are site or organ specific.

In response to these issues, reservoir delivery systems have beenexplored. Non-biodegradable drug delivery systems include, for example,Vitrasert® (Bausch & Lomb Inc.), a surgical implant that deliversganciclovir intraocularly; Duros® (Alza Corp.), surgically implantedosmotic pump that delivers leuprolide actetate to treat advancedprostate cancer; and Implanon™ (Organon USA Inc.), a type of subdermalcontraceptive implant.

Biodegradable implants include, for example, Lupron Depot® (leuprolideacetate, TAP Pharm. Prods., Inc.), a sustained-releasemicrosphere-suspension injection of luteinizing hormone-releasinghormone (LH-RH) analog for the treatment of prostate cancer; and thePosurdex® dexamethasone anterior segment drug delivery system (Allergan,Inc.) (commercial licensure pending FDA approval).

Additionally, polyethylene glycol conjugations (pegylation) to reducethe frequency of administration are now in use. One example is Macugen®(pegaptanib sodium injection, (OSI) Eyetech, Inc./Pfizer Inc.), apegylated anti-VEGF aptamer, for use in treating wet maculardegeneration.

There remains a need for a more economical, practical, and efficient wayof producing and manufacturing drug delivery systems that could be usedlocally or systemically, in solid, semi-solid, or liquid formulations.

SUMMARY OF THE INVENTION

An object of the present invention provides for economical, practical,and efficient drug delivery systems. According to the present invention,this drug delivery system is produced easily, delivered easily to thesite of indication, and is both biocompatible and biodegradable. Morespecifically, the formulations of the present invention provide fornovel therapies that are easily manipulated and injected or implanted byqualified medical practitioners. The formulations deliver therapeuticand non-toxic levels of active agents over the desired extended timeframe, primarily at the site of implantation. The formulations are bothbiocompatible and biodegradable, and disappear harmlessly afterdelivering active agent to the desired site.

One embodiment of the present invention provides for a pharmaceuticalformulation for implantation into a patient for the sustained release ofan active agent comprising a biocompatible, biodegradable excipient andan active agent or pharmaceutically acceptable salt thereof. In anaspect of the invention, the formulation is capable of being implantedby injection.

Another embodiment of the invention provides for a pharmaceuticalformulation for implantation into a patient for the sustained release ofan active agent comprising a biocompatible, biodegradable excipient andan active agent or pharmaceutically acceptable salt thereof, whereinsaid formulation exhibits an in vitro dissolution profile wherein about2% to about 100% of the active agent is released over a period rangingfrom about 1 day to at least 365 days.

Yet another embodiment provides for a pharmaceutical formulation forimplantation into a patient for the sustained release of an active agentcomprising a biocompatible, biodegradable excipient and an active agentor pharmaceutically acceptable salt thereof, wherein about 2% to about60% of the active agent is released over a period ranging from about 1day to about 105 days. Alternatively, about 2% to about 100% of theactive agent may be released over a period of about 25 days. Or about 2%to about 85% of the active agent may be released over a period of about30 days to about 60 days. In another embodiment, about 2% to about 60%of the active agent is released over a period ranging from about 80 daysto about 100 days.

In another aspect of the invention, the formulation comprises an activeagent at a concentration from about 5% to about 50% of the implant andincludes a biodegradable, biocompatible excipient at a concentration ofat least about 5% percent of the implant.

In another embodiment, the biocompatible, biodegradable excipient may bechosen from tocopherol isomers and/or their esters, tocotrienols and/ortheir esters, benzyl benzoate, esters of benzoic acid with straight,branched, or cyclic chain aliphatic alcohols having one to twenty carbonatoms wherein one of the hydrogen atoms on the aliphatic chain isreplaced with a hydroxyl group, tocopherol isomer acetates, succinatesand nicotinates, tocotrienol isomer acetates, succinates andnicotinates, the mono, di, and tri esters of O-acetylcitric acid orO-propionylcitric acid or O-butyrylcitric acid with C₁ to C₁₀ straightand branched chain aliphatic alcohols, the mono, di, and tri esters ofcitric acid with C₁ to C₁₀ straight and branched chain aliphaticalcohols, dibenzoate esters of poly(oxyethylene) diols having low watersolubility, poly(oxypropylene)diols having low water solubility,dimethyl sulfone, liquid and semisolid polycarbonate oligomers, ormixtures of two or more these. In an aspect of the invention, the liquidto semisolid polycarbonate oligomers includes those prepared by thepolymerization of trimethylene carbonate [poly(1,3-propanediolcarbonate)], the ester exchange polymerization of diethylene carbonatewith aliphatic diols or polyoxyalkane diols [poly(di-1,2-propyleneglycol carbonate), and poly(tri-1,2-propylene glycol carbonate)].

An aspect of the invention provides for a controlled and sustained drugdelivery system for the posterior segment of the eye, comprised of abiodegradable and biocompatible liquid matrix for direct injection. Aparticular aspect of the invention provides for compositions comprisingeither dexamethasone or triamcinolone acetonide and benzyl benzoate. Inanother aspect of this embodiment, dexamethasone or triamcinoloneacetonide is released into the vitreous of the eye in an amount rangingfrom about 20 μg/ml to less than about 1.0 μg/ml over a period of aboutsixty days to about ninety days.

Another embodiment of the present invention provides for abiocompatible, biodegradable, syringeable liquid, implantable solid, andinjectable gel sustained release formulations of therapeutic agents forbrain tumors that may be inserted directly into brain tumors. Theseformulations comprise novel biocompatible and biodegradable syringeableliquid, implantable cohesive solids, and injectable gel formulationsconveniently placed inside brain tumors for the sustained release ofbeneficial agents are obtained by admixing one or more of the excipientsof the present invention with one or more of established and new agentsfor the treatment of brain tumors, including anti-neovascularizationsteroids.

The active agent envisioned in an embodiment of the present invention isone selected from one or more of the group consisting of analgesics,anesthetics, narcotics, angiostatic steroids, anti-inflammatorysteroids, angiogenesis inhibitors, nonsteroidal anti-inflammatories,anti-infective agents, antibiotics, antifungals, antimalarials,antitublerculosis agents, antivirals, alpha androgenergic agonists, betaadrenergic blocking agents, carbonic anhydrase inhibitors, mast cellstabilizers, miotics, prostaglandins, antihistamines, antimicrotubuleagents, antineoplastic agents, antipoptotics, aldose reductaseinhibitors, antihypertensives, antioxidants, growth hormone agonists andantagonists, vitrectomy agents, adenosine receptor antagonists,adenosine deaminase inhibitors, glycosylation antagonists, anti-agingpeptides, topoisemerase inhibitors, anti-metabolites, alkylating agents,anti-andrigens, anti-oestogens, oncogene activation inhibitors,telomerase inhibitors, antibodies or portions thereof, antisenseoligonucleotides, fusion proteins, luteinizing hormone releasinghormones agonists, gonadotropin releasing hormone agonists, tyrosinekinase inhibitors, epidermal growth factor inhibitors, ribonucleotidereductase inhibitors, cytotoxins, IL2 therapeutics, neurotensinantagonists, peripheral sigma ligands, endothelin ETA/receptorantagonists, antihyperglycemics, anti-glaucoma agents, anti-chromatinmodifying enzymes, insulins, glucagon-like-peptides, obesity managementagents, anemia therapeutics, emesis therapeutics, neutropaeniatherapeutics, tumor-induced hypercalcaemia therapeutics, bloodanticoagulants, immunosuppressive agents, tissue repair agents,psychotherapeutic agents, botulinum toxins, essential fatty acids, andnucleic acids such as siRNA and RNAi.

In another embodiment of the invention, the active agent or excipientmay be an omega-3 fatty acid or an ester thereof. Another embodiment ofthe present invention provides for a formulation comprising anonpolymeric, biodegradable, bioabsorbable excipient and the activeagent is one or more antioxidants, either alone or included with one ormore steroids and/or quinolone anti-infectives. Still another embodimentprovides for the transdermal delivery of active agents, for example,insulin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents dissolution profiles of dexamethasone (Dex) from twoformulations of Dex/poly(1,3-propanediol carbonate)I.

FIG. 2 presents dissolution profiles of Dex from two formulations ofDex/poly(1,3-propanediol carbonate)II.

FIG. 3 represents dissolution profiles of Dex from three formulations ofDex/poly(di-1,2 propylene glycol carbonate).

FIG. 4 depicts dissolution profiles of Dex from two formulations ofDex/poly(tri-1,2 propylene glycol carbonate).

FIG. 5 depicts dissolution profiles of Dex released from threeformulations of Dex/benzyl benzoate.

FIG. 6 depicts dissolution profiles of Dex released from threeformulations of Dex/diethylene glycol dibenzoate.

FIG. 7 depicts dissolution profiles of triamcinolone acetonide releasedfrom three formulations of triamcinolone acetonide/diethylene glycoldibenzoate.

FIG. 8 depicts dissolution profiles of Dex released from threeformulations of Dex/d-tocopherol, and d1-tocopheryl acetate.

FIG. 9 depicts a dissolution profile of Dex released from aDex/diethylene glycol dibenzoate formulation.

FIG. 10 depicts a dissolution profile of Dex released from a Dex/benzylbenzoate formulation.

FIG. 11 depicts a dissolution profile of Dex released from aDex/tocopheryl succinate formulation.

FIG. 12 depicts a dissolution profile of Dex and Ciprofloxacin from a1:1 formulation of those components in benzyl benzoate (Panel A) and a3:1 formulation of Dex and Ciprofloxacin in benzyl benzoate (Panel B).

FIG. 13 depicts the concentration of Dex released into the vitreoushumor from two formulation of Dex in benzyl benzoate.

FIG. 14 represents a histopathological slide of rabbit eye tissue thirtydays after a posterior segment injection of a formulation of 25% Dex inbenzyl benzoate.

FIG. 15 depicts the vitreous concentration of tramcinolone acetonide(TA) released from a TA:benzyl benzoate composition.

FIG. 16 depicts the in vivo release of Dex released into the aqueoushumor from a Dex:d1-alpha tocopherol succinate formulation.

FIG. 17 depicts the dissolution of Dex from a Dex:acetone:tocopherolsuccinate formulation applied to solid surfaces.

FIG. 18 shows the dissolution profile of cyclosporin from a cyclosporin:tocopherol succinate formulation.

FIG. 19 depicts an in vivo release profile of cyclosporin from atocopherol succinate:cyclosporin formulation implanted the anteriorchamber of a New Zealand White (NZW) rabbit.

FIG. 20 depicts an in vivo release profile of cyclosporin from atocopherol succinate:cyclosporin formulation implanted the posteriorsegment of a NZW rabbit eye.

FIG. 21 shows an in vivo release of cyclosporine from a tocopherolsuccinate:cyclosporin formulation implanted in the peritoneal cavity ofa rat.

FIG. 22 plots in vivo blood glucose levels in mice treated with atransdermal formulation of insulin in tocopheryl acetate.

FIG. 23 shows in vitro release of Dex from a pellet of 1.5 mg of 50/50wt Dex/tocopheryl succinate.

FIG. 24 presents a bar graph reflecting brain tumor volume followingeither resection, or resection and subsequent treatment with Dex.

FIG. 25 depicts the percent Dex released in vitro from a formulation of24% Dex and Triethyl O-Acetyl Citrate (TEAC).

FIG. 26 shows the percent Dex released in vitro from a formulation of20% Dex and TEAC/Tocopherol Acetate.

FIG. 27 illustrates the percent Dex released in vivo from a formulationof 10% Dex and TEAC injected into the rabbit eye anterior chamber (AC).

FIG. 28 presents the percent Dex released in vivo from a formulation of10% Dex and TEAC injected into the rabbit eye vitreous chamber/posteriorsegment.

FIG. 29 depicts the kinetics of Dex released in vivo from 80 μg of Dexin a formulation of 20% Dex and TEAC injected into the rabbit eye AC.

FIG. 30 depicts the kinetics of Dex released in vivo from 900 μg of Dexin a formulation of 20% Dex and TEAC injected into the rabbit eye AC.

FIG. 31 shows the in vivo release of Ciprofloxacin from a 20%Ciprofloxacin/TEAC formulation injected into the AC of a rabbit eye.

FIG. 32 presents the in vivo release of Cyclosporin A (CsA) from aCsA/tocopherol formulation injected into the AC of a rabbit eye.

FIG. 33 presents the in vivo release of Cyclosporin A (CsA) from aCsA/TEAC formulation injected into the vitreous of a rabbit eye.

FIG. 34 illustrates the in vivo release of active monoclonal antibody(Mab) from three different formulations tested in the vitreous cavity ofrabbit eyes.

FIG. 35 reflects the intraocular sustained release of rapamycin fromrapamycin:TEAC formulation injected into the vitreous cavity of rabbiteyes.

FIG. 36 shows the sustained release of ketorolac acid from a formulationof ketorolac acid:benzyl benzoate injected into the anterior chamber ofthe rabbit eye.

FIG. 37 shows the sustained release of ketorolac acid into the vitreousfrom either a formulation of ketorolac acid:benzyl benzoate or ketorolacacid:TEAC injected into the vitrous of the rabbit eye

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc, described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention, which is defined solely by the claims.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. Thus, for example, the reference to an excipient is areference to one or more such excipients, including equivalents thereofknown to those skilled in the art. Other than in the operating examples,or where otherwise indicated, all numbers expressing quantities ofingredients or reaction conditions used herein should be understood asmodified in all instances by the term “about.” The term “about” whenused in connection with percentages may mean ±1%.

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention, but are not to providedefinitions of terms inconsistent with those presented herein. Thesepublications are provided solely for their disclosure prior to thefiling date of the present application. Nothing in this regard should beconstrued as an admission that the inventors are not entitled toantedate such disclosure by virtue of prior invention or for any otherreason. All statements as to the date or representation as to thecontents of these documents is based on information available to theapplicants and do not constitute any admission as to the correctness ofthe dates or contents of these documents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood to one of ordinaryskill in the art to which this invention pertains.

The present invention relates to novel biocompatible, biodegradablesustained release formulations. In various aspects of the invention,these formulations are syringeable liquids, mechanically cohesivesolids, injectable gels, or emulsified micells (oil in water or water inoil). A desirable feature of these liquid, solid, and gel formulationsis that they maintain a single bolus or pellet shape at the site oftheir placement. That is, they do not break up as a multitude of smallerdroplets or particles that migrate away from their intended point ofplacement and/or by virtue of a resultant increase in surface areagreatly alter the intended release rate of their drug content.

The formulations of the present invention provide for novel therapiesthat are easily manipulated and injected or implanted by qualifiedmedical practitioners. The formulations deliver therapeutic andnon-toxic levels of active agents over the desired extended time frame,primarily at the site of implantation. The formulations are bothbiocompatible and biodegradable, and disappear harmlessly afterdelivering active agent to the desired site.

The present invention relates generally, but not totally, to the use offormulations that are of limited solubility, biocompatible, andbiodegradable (LSBB), which may also be syringeable, for controlled andsustained release of an active agent or a combination of active agents.Solid, gel or injectable, controlled-sustained release systems can befabricated by combining LSBB and an active agent. Systems can combinemore than one biodegradable component as well as more than one activeagent. Solid forms for implantation can be produced by tableting,injection molding or by extrusion. Gels can be produced by vortex ormechanical mixing. Injectable formulations can be made by pre-mixing ina syringe or mixing of the LSBB and the active agent before or at thetime of administration. Formulations may serve as coating for stents orother implants by, for example, dipping the stent in a liquid form ofthe formulation and then drying it.

In an aspect of the present invention, novel biocompatible andbiodegradable syringeable liquid, implantable cohesive solids, andinjectable gel formulations conveniently placed on or within the humanor animal body for the sustained release of active agents, are obtainedby admixing one or more excipients, such as, for example: benzylbenzoate, esters of benzoic acid with straight, branched, or cyclicchain aliphatic alcohols having one to twenty carbon atoms wherein oneof the hydrogen atoms on the aliphatic chain is replaced with a hydroxylgroup (e.g., such alcohols as methanol, ethanol, n-propanol, i-propanol,n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol,neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol,n-decanol, and the like), tocopherol isomer acetates, succinates andnicotinates, tocotrienol isomer acetates, succinates and nicotinates,the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitricacid or O-butyrylcitric acid with C₁ to C₁₀ straight and branched chainaliphatic alcohols, the mono, di, and tri esters of citric acid with C₁to C₁₀ straight and branched chain aliphatic alcohols, omega-3 fattyacids and their esters of C₁ to C₈ straight and branched chain aliphaticalcohols, dibenzoate esters of poly(oxyethylene) diols having low watersolubility, poly(oxypropylene)diols having low water solubility,dimethyl sulfone, liquid and semisolid polycarbonate oligomers, with alarge number of established and new active agents. In an aspect of theinvention, the liquid to semisolid polycarbonate oligomers include thoseprepared by the polymerization of trimethylene carbonate[poly(1,3-propanediol carbonate)], the ester exchange polymerization ofdiethylene carbonate with aliphatic diols or polyoxyalkane diols[poly(di-1,2-propylene glycol carbonate), and poly(tri-1,2-propyleneglycol carbonate)].

In another aspect of the invention, the solid form generally containsabout 1% to about 60% of an LSBB, the gel form generally contains about20% to about 80% of an LSBB, and an injectable form (which may be a gelor liquid form) generally contains about 30% to about 99.9% of an LSBB.

Liquid and solid LSBB formulations can be implanted, for example,surgically, by trocar, or by needle introduction. The formulations canbe placed into body cavities such as joints by methods well-known in theart (typically using the procedures outlined by Cardone & Tallia, Am.Family Physician, 66 (2), 283-92 (2002); 66 (11), 2097-100 (2002); 67(10), 2147-52 (2003); 68 (7), 1356-62 (2003); 67 (4), 745-50 (2003));intraocular (chambers such as the anterior chamber and posterior segmentof the eye); intratumoral injection into the prostate tumor (typicallyusing a procedure similar to that described by Jackson et al., 60 (5)Cancer Res., 4146-51 (2000)); intratumoral injection into inoperabletumors (such as gliomas) in the brain (typically using a proceduresimilar to that described by Emerich et al., 17 (7) Pharm Res, 767-75(2000)); injection or insertion into an intravertebral disc or discspace; injection into peritoneal cavity, or intranasal, intrathecal,subcutaneous or intramuscular injection, injection into the epidural,subdural and/or subarachnoid space; or the formulation may be injectedor inserted directly into the cerebral spinal fluid through the spinalcanal or into the CNS ventricular system.

Additionally, for localized active agent delivery, the system of thepresent invention may be surgically implanted at or near the site ofaction. This may be useful when it is used, for example, in treatingocular conditions, primary tumors, rheumatic and arthritic conditions,and chronic pain.

It is contemplated that these LSBB/active agent compositions can beapplied to the following, but not limited to, systems of the human oranimal body: muscular, skeletal, nervous, autonomic nervous, vascular,lymphatic, digestive, respiratory, urinary, female reproductive, malereproductive, endocrine or intraparenchymal, to provide a wide varietyof sustained therapies.

Specific areas of the human or animal body to be targeted for injectionor implantation or topical applications of these LSBB/active agentscompositions include, but are not limited to: heart, brain, spinalnerves, vertebral column, skull, neck, head, eye, ear organs of hearingand balance, nose, throat, skin, viscera, hair, shoulder, elbow, hand,wrist, hip, knee, ankle, foot, teeth, gums, liver, kidney, pancreas,prostate, testicles, ovaries, thymus, adrenal glands, pharynx, larynx,bones, bone marrow, stomach, bowel, upper and lower intestines, bladder,lungs, mammaries. Surgical implantation into the eye, for example, isknown in the art as described in U.S. Pat. No. 6,699,493; U.S. Pat. No.6,726,918; U.S. Pat. No. 6,331,313; U.S. Pat. No. 5,824,072; U.S. Pat.No. 5,766,242; U.S. Pat. No. 5,443,505; U.S. Pat. No. 5,164,188; U.S.Pat. No. 4,997,652; and U.S. Pat. No. 4,853,224.

Solid LSBB formulations, for example, may be implanted directly intoparenchymal tissues such as the brain, spinal cord, or any part of theCNS system, into the kidney, liver, spleen, pancreas, lymph nodes aswell as tumors. Gel LSBB systems may be applied to surface tissues suchas the skin, or as coating on surfaces of parenchymal organs to beabsorbed, or be applied directly on the cornea, conjunctiva and on thesclera for delivery of active agent onto the surface of andintraocularly to the eye. Injectable LSBB formulations are less invasiveand can be delivered, for example, through a 30 gauge needle into theeye, or through larger needles into cavities such as joints.

The system according to the present invention has particularapplicability in providing a controlled and sustained release of activeagents effective in obtaining a desired local or systemic physiologicalor pharmacological effect relating at least to the following areas:treatment of cancerous primary tumors, chronic pain, arthritis,rheumatic conditions, hormonal deficiencies such as diabetes anddwarfism, modification of the immune response such as in the preventionand treatment of transplant rejection and in cancer therapy. The systemis also suitable for use in treating HIV and HIV related opportunisticinfections such as CMV, toxoplasmosis, Pneumocystis carinii, andMycobacterium avium-intercellulare. The system may be used to deliveryan active agent effective in treating fungal infection of the mouth. Ifsuch a use is desired, the system may be designed to have a shapesuitable for implanting into a tooth.

LSBB formulations are also useful for treating ocular conditions such asglaucoma, PVR, diabetic retinopathy, uveitis, retinal edema, veinocclusion, macular degeneration, Irvine-Gass Syndrome and CMV retinitis,corneal diseases such as keratitis, and corneal transplantationrejection. The formulations may also be prepared as control-release eyedrops for dry-eye or for controlling the immune response. Regardingcontrol of immune responses, the formulations may contain one or more ofcyclosporine, sirolimus, or tacrolimus. Other intraocular uses includeglaucoma treatments (e.g., formulations including timolol), antibioticdelivery, antibody delivery, and antiproliferatives delivery (e.g.,paclitaxel).

Other uses of the formulations include, for example, mediating homograftrejection with formulations comprising sirolimus or cyclosporine. Localcancer therapy may be delivered to, for example, the kidney or liver,using in formulations comprising, for example, adriamycin or smallepidermal growth factors. Prostate cancer may be treated withformulations including fenasteride. Cardiac stents implants, centralnervous system implants (e.g., spinal implants), orthopedic implants,etc., may be coated with formulations including growth ordifferentiation factors, anti-inflammatory agents, or antibiotics.

Additionally, the pharmaceutical formulations herein provide for methodsfor the management of skin wrinkles, or bladder, prostatic and pelvicfloor disorders by implanting, by injection, a pharmaceuticalformulation comprising a biodegradable, biocompatible excipient andbotulinum toxins into a strategic position in the skin or bladder,prostate or pelvic floor region to provide controlled and sustainedrelease of a therapeutically effective but non-toxic level of thebotulinum toxins within the effected areas. The pharmaceuticalformulations herein also provide methods for the management of uterinefibroids by implanting, by injection, a pharmaceutical formulationcomprising a biodegradable, biocompatible excipient and suitabletherapeutic agent, such as pirfenidone, human interferon-alpha, GnRHantagonists, Redoxifene and estrogen-receptor modulators, into strategicpositions inside the fibroids to provide controlled and sustainedrelease of therapeutically effective, but non-toxic levels, of thetherapeutic agents within the fibroids.

The technology of the present application is useful in overcoming thedifficulties reported in some cases of achieving therapeutic efficacy,as experienced in current administrations requiring large doses ofmedications that may result in toxic side effects. An important exampleof this problem is the current clinical practice of intravitrealinjections of microcrystalline triamcinolone acetonide (TA) for thetreatment of intraocular neovascular, oedematous, or inflammatorydiseases. See Jonas et al., 24 (5) Prog Retin Eye Res. 587-611 (2005),and references therein. The therapy requires the presence of a solutionof the proper TA concentration in the vitreous chamber for periods ofsix months to a year and possibly longer. The therapeutic vitrealconcentrations of TA seem to be at 1.0 μg/ml or below (Matsuda et al.,46 Invest Opthalmol Vis Sci. 1062-1068 (2005)) whereas harmfulcomplications (glaucoma, cataracts, cytotoxicity) can arise when TAconcentrations continuously exceed 10 μg/ml over an extended period oftime. See Gillies et al., 122 (3) Arch Opthalmol. 336-340 (2004); Jonaset al., 15 (4) Eur J Opthalmol. 462-4 (2005); Yeung et al, 44 InvestOpthalmol Vis Sci. 5293-5300 (2003). The desire to limit TAadministration to one or two injections per year (because of patientdiscomfort coupled with the possibility of endophthalmitis (see Bucheret al., 123 (5) Arch Opthalmol. 649-53 (2005)), conflicts with theability of supplying enough TA crystals without excursions into toxicconcentrations. The novel compositions of this invention solve thisproblem by encompassing the desired amounts of TA in an injectable,biocompatible, bioerodable medium that continuously regulates therelease of safe, therapeutic levels of intravitreal TA for periods ofsix months or more.

Further regarding ocular conditions, metabolic and inflammationconditions in the posterior segment of the eye have been extremelydifficult to treat. Such conditions as proliferative vitreoretinopathy(PVR), uveitis, cystoid macular edema (CME), diabetes, and maculardegeneration are major causes of blindness. Conventional methods of drugdelivery, including topical, periocular, subconjunctival or systemicadministration, have had limited success due in large part to poor drugpenetration (due to the blood-eye barrier) and toxic side effects. Oneefficient way of delivering a drug to the posterior segment is to placeit directly into the vitreous cavity. Intravitreal drug injections haveshown promising results in animals and in humans, but repeated andfrequent injections have had to be performed to maintain therapeuticlevels.

For example, direct injection of corticosteroids, particularlytriamcinolone acetonide, has been effective particularly in selected wetmacular degeneration and in diabetic retinal edemas. Because of thedrugs' short half-life in the eye, frequent injections are required.Moreover, because the drug is being given in a bolus, uncontrolled highand then low drug concentration levels are encountered. As aconsequence, adverse reactions such as infection, glaucoma, cataractformation, retinal detachment and intraocular bleeding have been commonadverse occurrences. Vitrasert® (Bausch & Lomb) is a six- to eight-monthreservoir system to treat CMV retinitis with the antiviral gancyclovir.This is a non-biodegradable system and must be both inserted and removedsurgically. Similarly, Posurdex® (Allergan, Inc.) is a one-monthbiodegradable delivery system that must be implanted surgically into theeye, and contains dexamethasone and poly(lactic-co-glycolic acid) (PLGA)for the treatment of posterior segment pathologies.

Hence, one embodiment of the present invention provides for anintraocular controlled and sustained drug delivery system for theposterior segment of the eye. It is comprised of a biodegradable andbiocompatible liquid matrix containing a microdispersed drug or mixtureof drugs, and can be injected directly into the posterior segment with arelatively small needle. The duration of drug delivery can be as shortas a few days to many months and up to one year or longer, and thematrix gradually and safely dissipates over time so that there is noneed to remove it. An example embodiment comprises dexamethasone andbenzyl benzoate. In this system, intravitreal levels of dexamethasonewith a 25% formulation in 50 μl delivers a mean vitreous level ofapproximately 8.0 μg/ml over a three-month period. In comparison, a 25μl injection delivers a mean vitreous level of approximately 4.0 μg/mlover a sixty day period. This composition is biocompatible,biodegradable, non-toxic, easy to manufacture, easy to deliver, andflexible in terms of therapeutic dose and duration of delivery.

Another aspect of the invention provides for a formulation for limitingtissue rejection following corneal transplant. Corneal transplant, alsoknown as a corneal graft, or as a penetrating keratoplasty, involves theremoval of the central portion (called a button) of the diseased corneaand replacing it with a matched donor button of cornea. Corneal graftsare performed on patients with damaged or scarred corneas that preventacceptable vision. This may be due to corneal scarring from disease ortrauma. Formulations of the present invention useful in cornealtransplant contexts may include rapamycin, cyclosporin, or a combinationof these active agents.

Further regarding cyclosporin and rapamycin, these active agents may beused in the anterior segment and/or the posterior segment of the eye.These are antiimmune drugs that have antiinflammatory properties,antirejections properties, antifibrosis activities, and antineogenesisproperties. As provided for herein, formulations of these agents eitheralone or in combination may be prepared for use in the used in theanterior segment for corneal rejection (organ rejection) or anyinflammatory conditions. Formulations may also be prepared for use inthe posterior segment or back of the eye for indications such as maculardegeneration, antineogenesis which occurs in macular degeneration, orfor cellular transplants or stem cell transplants for repair or inmaintaining the health of the retina, choroid etc.

A wide variety of other disease states are known by those of ordinaryskill in the art, such as those described in Goodman & Gilman, THEPHARMACOLOGICAL BASIS OF THERAPEUTICS (McGraw Hill, 2001), andREMINGTON'S PHARMACEUTICAL SCIENCES (Lippincott Williams & Wilkins; 20thed., 2000). Those to which the present invention may be applied may bedetermined by those with ordinary skill in the art without undueexperimentation.

Suitable classes of active agents for use in the system of the presentinvention include, but are not limited to the following:

Peptides and proteins such as cyclosporin, insulins,glucagon-like-peptides, growth hormones, insulin related growth factor,botulinum toxins (Botox, Allergan), antibodies, and heat shock proteins;

Anesthetics and pain killing agents such as lidocaine and relatedcompounds, and benzodiazepam and related compounds;

Anti-cancer agents such as 5-fluorouracil, methotrexate and relatedcompounds;

Anti-inflammatory agents such as 6-mannose phosphate;

Anti-fungal agents such as fluconazole and related compounds;

Antiviral agents such as trisodium phosphomonoformate,trifluorothymidine, acyclovir, cidofovir, ganciclovir, ddI, and AZT;

Cell transport/mobility impending agents such as colchicines,vincristine, cytochalasin B, and related compounds;

Anti-glaucoma drugs such as beta-blockers: timolol, betaxolol, andatenolol;

Immunological response modifiers such as muramyl dipeptide and relatedcompounds;

Steroidal compounds such as dexamethasone, prednisolone, triamcinoloneand related compounds; and

Carbonic anhydrase inhibitors such as acetazolamide, brinzolamide,dorzolamide, and timolol maleate.

In addition to the above agents, other active agents which are suitablefor administration, especially to the eye and its surrounding tissues,to produce a local or a systemic physiologic or pharmacologic effect canbe used in the system of the present invention. Examples of such agentsinclude antibiotics such as tetracycline, chloramphenicol,ciprofloxacin, ampicillin and the like.

Any pharmaceutically acceptable form of the active agents of the presentinvention may be employed in the practice of the present invention,e.g., the free base or a pharmaceutically acceptable salt or esterthereof. Pharmaceutically acceptable salts, for instance, includesulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate,citrate, phosphate, and the like.

The active agents may also be used in combination with pharmaceuticallyacceptable carriers in additional ingredients such as antioxidants,stabilizing agents, and diffusion enhancers. For example, where wateruptake by the active agent is undesired, the active agent can beformulated in a hydrophobic carrier, such as a wax or an oil, that wouldallow sufficient diffusion of the active agent from the system. Suchcarriers are well known in the art.

In another aspect of the invention, a low solubility active agent may becombined with a biodegradable, biocompatible excipient of highersolubility to result in an LSBB formulation. For example, dimethylsulfone may be used as a binder in an LSBB formulation of a limitedsolubility active agent. Hence, the use of a soluble excipient in anLSBB formulation is within the scope of the present invention.

In one embodiment, the active agents, e.g., proteins, may be formulatedin a glassy matrix of sugar which tends to protect the active agent fromhydrolytic degradation and extend their shelf life and eliminate theneed for cold storage. See, for example, Franks, Long-Term Stabilizationof Biologicals, 12 Bio/Technology 253-56 (1994), the contents of whichare hereby incorporated by reference.

Proteins may be formulated in a glass matrix by removing water from ahomogeneous solution thereof. The water can be removed either byevaporation or by rapidly cold quenching the solution. The process iscommonly referred to as vitrification. As water is removed from thesolution, it becomes increasingly viscous until a “solidified” liquidcontaining the proteins is obtained. The “solidified” liquid isgenerically called glass.

Glasses have a number of unique physical and chemical properties whichmake them ideal for active agent formulation. Among them, the mostimportant is that the solidified liquid retains the molecular disorderof the original solution. This disorder contributes to the glasses'long-term stability by preventing crystallization and chemical reactionsof the proteins encased therein.

Sugars can also play an important part in stabilizing proteinformulations. In solution, they are known to shift the denaturationequilibrium of proteins toward the native state. Most sugars,particularly low molecular weight carbohydrates, are also known tovitrify easily and to provide a glassy matrix that retards inactivatingreactions of the proteins.

For illustrative purposes, the glassy sugar matrix for use in the systemaccording to the present invention can be made by compressing alyophilized mix of a protein with sugar and a buffer, and optionally,binders.

Examples of proteins and proteinaceous compounds which may be formulatedand employed in the delivery system according to the present inventioninclude those proteins which have biological activity or which may beused to treat a disease or other pathological condition. They include,but are not limited to antibodies, growth hormone, Factor VIII, FactorIX and other coagulation factors, chymotrypsin, trysinogen,alpha-interferon, beta-galactosidase, lactate dehydrogenase, growthfactors, clotting factors, enzymes, immune response stimulators,cytokines, lymphokines, interferons, immunoglobulins, retroviruses,interleukins, peptides, somatostatin, somatotropin analogues,somatomedin-C, Gonadotropic releasing hormone, follicle stimulatinghormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide,nafarelin and geserelin, LHRH agonists and antagonists, growth hormonereleasing factor, callcitonin, colchicines, gonadotropins such aschorionic gonadotropin, oxytocin, octreotide, somatotropin plus andamino acid, vasopressin, adrenocorticotrophic hormone, epidermal growthfactor, prolactin, somatotropin plus a protein, cosyntropin, lypressin,polypeptides such as thyrotropin releasing hormone, thyroid stimulationhormone, secretin, pancreozymin, enkephalin, glucagons, and endocrineagents secreted internally and distributed by way of the bloodstream.

Other agents, such as α₁ antitrypsin, insulin, glucagon-like-peptides,and other peptide hormones, botulinum toxins (Botox®, Allergan, Inc.),adrenal cortical stimulating hormone, thyroid stimulating hormone, andother pituitary hormones, interferons such as α, β, and δ interferon,erythropoietin, growth factors such as GCSFm GM-CSF, insulin-like growthfactor 1, tissue plasminogen activator, CF4, dDAVP, tumor necrosisfactor receptor, pancreatic enzymes, lactase, interleukin-1 receptorantagonist, interleukin-2, tumor suppresser proteins, cytotoxicproteins, viruses, viral proteins, recombinant antibodies, portions ofantibodies, and antibody fragments and the like may be used. Analogs,derivatives, antagonists, agonists, and pharmaceutically acceptablesalts of the above may also be used.

Other active agents encompassed in the present invention includeprodrugs. Because prodrugs are known to enhance numerous desirablequalities of pharmaceuticals (e.g., solubility, bioavailability,manufacturing, etc.) the pharmaceutical dosage forms of the presentinvention may contain compounds in prodrug form. Thus, the presentinvention is intended to cover prodrugs of the presently claimed activeagents, methods of delivering the same, and compositions containing thesame.

Analogs, such as a compound that comprises a chemically modified form ofa specific compound or class thereof, and that maintains thepharmaceutical and/or pharmacological activities characteristic of saidcompound or class, are also encompassed in the present invention.Similarly, derivatives such as a chemically modified compound whereinthe modification is considered routine by the ordinary skilled chemist,such as an ester or an amide of an acid, protecting groups, such as abenzyl group for an alcohol or thiol, and tert-butoxycarbonyl group foran amine, are also encompassed by the present invention.

The active agents are useful for the treatment or prevention of avariety of conditions including, but not limited to hemophilia and otherblood disorders, growth disorders, diabetes, obesity, leukemia,hepatitis, renal failure, HIV infection, hereditary diseases such ascerebrosidase deficiency and adenoine deaminase deficiency,hypertension, septic shock, autoimmune disease such as multiplesclerosis, Graves disease, systemic lupus erythematosus and rheumatoidarthritis, shock and wasting disorders, cystic fibrosis, lactoseintolerance, Crohn's disease, inflammatory bowel disease,gastrointestinal and other cancers, cancerous or benign tumors, andmanagement of bladder, prostatic, and pelvic floor disorders, anduterine fibroid (submucosal, subserosal, intramural, parasitic myomas,and seedling myomas) management (using for example but not limited topirfenidone, human interferon-alpha, GnRH antagonists, Redoxifene,estrogen-receptor modulators). Additionally, the formulations of thepresent invention may be used to treat intracranial aneurysms by, forexample, introducing fibrogen or plasmin.

It is further contemplated that topical formulations of these LSBBs withactive agents can be applied for the transdermal administration ofcontraceptives, insulin or GLP-1, transdermal application for alopeciatreatment or delivery of aspirin or other small molecules, smokingcessation agents, anti-obesity agents, antivirals (herpes therapies),agents for psoriasis therapies, agents for alopecia therapies, agentsfor acne therapies, agents for erectile disfunction and antiparasiticagents, to name a few.

The protein compounds useful in the formulations of the presentinvention can be used in the form of a salt, preferably apharmaceutically acceptable salt. Useful salts are known to thoseskilled in the art and include salts with inorganic acids, organicacids, inorganic bases, or organic bases.

Sugars useful for preparing the glassy matrix discussed previouslyinclude, but are not limited to, glucose, sucrose, trehalose, lactose,maltose, raffinose, stachyose, maltodextrins, cyclodextrins, sugarpolymers such as dextrans and their derivatives, ficoll, and starch.

Buffers useful for formulating the glassy matrix include, but notlimited to MES, HEPES, citrate, lactate, acetate, and amino acid buffersknown in the art.

The LSBB system comprising the glassy sugar matrix may be constructed ofa bioerodible polymer with low water permeability. Such polymers includepoly(glycolic acid), poly(lactic acid), copolymers of lactic/glycolicacid, polyorthoesters, polyanhydrides, polyphosphazones,polycaprolactone. These polymers may be advantageous because of theirslow erosion properties and low water uptake; thus, they should notundergo undue changes during the course of the active agent delivery.

Naturally occurring or synthetic materials that are biologicallycompatible with body fluids suitable for use in the present inventiongenerally include polymers such as polyethylene, polypropylene,polyethylene terephthalate, crosslinked polyester, polycarbonate,polysulfone, poly(2-pentene), poly(methylmethacrylate),poly(1,4-phenylene), polytetrafluoroethylene, andpoly-ethylene-vinylacetate (EVA).

In an aspect of the present invention, the excipient is alsobiodegradable or bioerodible. As used herein, the terms “bioerodible”and “biodegradable” are equivalent and are used interchangeably.Biodegradable excipients are those which degrade in vivo, and whereinerosion of the excipient over time is required to achieve the agentrelease kinetics according to the invention. Suitable biodegradableexcipients may include but are not limited to, for example,poly(glycolic acid), poly(lactic acid), copolymers of lactic/glycolicacid, polyorthoesters, polyanhydrides, polyphosphazones, polycarbonates,and polycaprolactone. The use of polylactic polyglycolic acid isdescribed in, for example, U.S. Pat. No. 6,699,493. See also U.S. Pat.No. 5,869,079.

In another aspect of the invention, the excipient is biocompatible,meaning that it does not have undue toxicity or cause eitherphysiologically or pharmacologically harmful effects. In another aspectof the invention, the excipient is biodegradable.

Examples of excipients that may be useful as biocompatible,biodegradable and/or bioerodible excipients in the present invention, asdetermined by one of ordinary skill in the art in light of thisspecification, without undue experimentation, include, but are notlimited to d-α-tocopherol; d,1-α-tocopherol; d-β-tocopherol;d,1-β-tocopherol; d-η-tocopherol; and d,1-η-tocopherol (includingacetate, hemisuccinate, nicotinate, and succinate-PEG ester forms ofeach of the foregoing, including a succinic-PEG ester such astocophersolan); tocotrienol isomers, and their esters; benzyl benzoate,esters of benzoic acid with straight, branched, or cyclic chainaliphatic alcohols having one to twenty carbon atoms wherein one of thehydrogen atoms on the aliphatic chain is replaced with a hydroxyl group(e.g., such alcohols as methanol, ethanol, n-propanol, i-propanol,n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol,neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol,n-decanol, and the like), tocotrienol isomer succinates and nicotinates;the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitricacid or O-butyrylcitric acid with C₁ to C₁₀ straight and branched chainaliphatic alcohols, the mono, di, and tri esters of citric acid with C₁to C₁₀ straight and branched chain aliphatic alcohols, dibenzoate estersof poly(oxyethylene) diols having low water solubility,poly(oxypropylene)diols having low water solubility, liquid andsemisolid polycarbonate oligomers, and dimethyl sulfone. The liquid tosemisolid polycarbonate oligomers may be those polycarbonate oligomersprepared by the polymerization of trimethylene carbonate[poly(1,3-propanediol carbonate)], the ester exchange polymerization ofdiethylene carbonate with aliphatic diols or polyoxyalkane diols[poly(di-1,2-propylene glycol carbonate), or poly(tri-1,2-propyleneglycol carbonate)].

Another example of biodegradable/biocompatible excipients useful in thepresent invention are “tocols”: a family of tocopherols and tocotrienolsand derivatives thereof. Tocopherols and tocotrienols are derivatives ofthe simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman. Tocopherolsare also known as a family of natural or synthetic compounds commonlycalled Vitamin E. Alpha-tocopherol is the most abundant and active formof this class of compounds. Other members of this class include β-, γ-,and δ-tocopherols and α-tocopherol derivatives such as tocopherylacetate, succinate, nicotinate, and linoleate. Useful tocotrienolsinclude d-δ-tocotreinols, and d-β-, d-γ-tocotrienols, and their esters.

In addition to the excipients listed above, the following excipientshaving very low viscosities are valued not only by themselves ascarriers of drugs for injectable sustained release (ISR) formulations,but also as additives to the ISR formulations of the excipients listedabove to reduce their viscosities and thereby improve syringeability.These include: perfluorodecalin; perfluorooctane; perfluorohexyloctane;the cyclomethicones, especially octamethylcyclotetrasiloxane;decamethylcyclopentasiloxane, and dodecamethylcyclohexasiloxanepolydimethylsiloxanes of viscosities below about 1000 cSt; diethylcarbonate; and dipropylcarbonate.

It is also contemplated that these liquid and solid LSBBs/active agentformulations can be coatings on implanted surfaces, such as but notlimited to, those on catheters, stents (cardiac, CNS, urinary, etc.),prosthesis (artificial joints, cosmetic reconstructions, and the like),tissue growth scaffolding fabrics, or bones and teeth to provide a widevariety of therapeutic properties (such as but not limited to,anti-infection, anti-coagulation, anti-inflammation, improved adhesion,improved tissue growth, improved biocompatibility). These surfaces canbe from a wide variety of materials, such as but not limited to, naturalrubbers, wood, ceramics, glasses, metals, polyethylene, polypropylene,polyurethanes, polycarbonates, polyesters, poly(vinyl acetates),poly(vinyl alcohols), poly(oxyethylenes), poly(oxypropylenes),cellulosics, polypeptides, polyacrylates, polymethacrylates,polycarbonates, and the like.

Active agents, or active ingredients, that may be useful in the presentinvention singly or in combination, as determined by one of ordinaryskill in the art in light of this specification without undueexperimentation, include but are not limited to:

Analgesics, Anesthetics, Narcotics such as acetaminophen; clonidine(Duraclon®, Roxane Labs.) and its hydrochloride, sulfate and phosphatesalts; oxycodene (Percolone™, Endo Pharm. Inc.) and its hydrochloride,sulfate, phosphate salts; benzodiazepine; benzodiazepine antagonist,flumazenil (Romazicon®, Roche U.S. Pharm.); lidocaine; tramadol;carbamazepine (Tegretol®, Novartis Pharm.); meperidine (Demerol®,Sanofi-Synthelabo, Inc.) and its hydrochloride, sulfate, phosphatesalts; zaleplon (Sonata®, Wyeth-Ayerst Labs.); trimipramine maleate(Surmontil®, Wyeth-Ayerst Labs.); buprenorphine (Buprenex®, ReckittBenckiser Pharm.); nalbuphine (Nubain®, Endo Pharm. Inc.) and itshydrochloride, sulfate, phosphate salts; pentazocain and hydrochloride,sulfate, phosphate salts thereof; fentanyl and its citrate,hydrochloride, sulfate, phosphate salts; propoxyphene ordextropropoxyphene and its hydrochloride and napsylate salts (Darvocet®,Eli Lilly & Co.); hydromorphone (Dilaudid®, Abbott Labs.) and itshydrochloride, sulfate, and phosphate salts; methadone (Dolophine®,Roxane Labs.) and its hydrochloride, sulfate, phosphate salts; morphineand its hydrochloride, sulfate, phosphate salts; levorphanol(Levo-Dromoran®, ICN Pharm., Inc.) and its tartrate, hydrochloride,sulfate, and phosphate salts; hydrocodone and its bitartrate,hydrochloride, sulfate, phosphate salts;

Angiostatic and/or Anti-inflammatory Steroids such as anecortive acetate(Retaane®, Alcon); tetrahydrocortisol;4,9(11)-pregnadien-17α,21-diol-3,20-dione and its -21-acetate salt;11-epicortisol; 17α-hydroxyprogesterone; tetrahydrocortexolone;cortisona; cortisone acetate; hydrocortisone; hydrocortisone acetate;fludrocortisone; fludrocortisone acetate; fludrocortisone phosphate;prednisone; prednisolone; prednisolone sodium phosphate;methylprednisolone; methylprednisolone acetate; methylprednisolone,sodium succinate; triamcinolone; triamcinolone-16,21-diacetate;triamcinolone acetonide and its -21-acetate, -21-disodium phosphate, and-21-hemisuccinate forms; triamcinolone benetonide; triamcinolonehexacetonide; fluocinolone and fluocinolone acetate; dexamethasone andits 21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its-21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide (Diamox®, American Cyanamid Co.);

Nonsteroidal Anti-inflammatories such as naproxin; diclofenac; celecoxib(Celebrex®, Pfizer); sulindac; diflunisal; piroxicam; indomethacin;etodolac; meloxicam; ibuprofen; ketoprofen; r-flurbiprofen (MyriadGenetics, Inc.); mefenamic; nabumetone; tolmetin, and sodium salts ofeach of the foregoing; ketorolac bromethamine; ketorolac tromethamine(Acular®, Allergan, Inc.); choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d, 1, and racemic isomers); methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid; tenoxicam; aceclofenac; nimesulide; nepafenac;amfenac; bromfenac; flufenamate; and phenylbutazone;

Angiogenesis Inhibitors such as squalamine, squalamine lactate (Evizon™,Genaear Corp.) and curcumin; Vascular endothelial growth factor (VEGF)inhibitors including pegaptanib (Macugen®, Eyetech/Pfizer), bevacizumab(Avastin®, Genentech, Inc.), concentrated shark cartilage extract(Neovastat®, AEterna Zentaris), PTK 787 (vatalanib, ScheringAG/Novartis), ribozyme anti-angiogenic (Angiozyme®, Sirma Therapeutics,Inc./Chiron Corp.); AZD 6474 (Zactima®, AstraZeneca AB Ltd.),anti-angiogenesis chimeric monoclonal antibody specific VEGF receptor 2(IMC-1C11, ImClone Sys. Inc.), isocoumarin2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3,Ilex Oncology Inc.), SU668 (Pfizer),isopropoxymethyl-12-(3-hydroxypropyl) ideno[2,1-a]pyrro [3,4-c]carbazole-5-one (CEP-5214, Cephalon), CEP-7055 (the N,N-dimethyl glycine esterprodrug of CEP-5214, Cephalon), and PTC299 (PTC Therapeutics); Integrinantagonists such as anti-α_(v)β₃ antibody (Vitaxin®, Medimmune Inc.);RDG peptide mimetics such as S137 and S247 (Pfizer), conformationallyconstrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides suchas ST1646 (Sigma Tau S.p.A.); DPC A803350 (Bristol-Myers Squibb), ando-guanidines (3D Pharmaceuticals Inc.); matrix metalloproteinaseinhibitors such as prinomastat (AG 3340, Pfizer), (ISV-616, InSiteVision), (TIMP-3, NIH); S3304 (Shionogi); BMS 275291(Celltech/Bristol-Myers Squibb); SC 77964 (Pfizer); ranibizumab(Lucentis®, Genentech, Inc.); ABT 518 (Abbott Labs.); CV 247 (IvyMedical); NX-278-L anti-VEGF aptamer (EyeTech Pharm.); 2′-O-mrthoxyethylantisense C-raf oncogene inhibitor (ISIS-13650, Isis Pharm., Inc./iCoTherapeuticals, Inc.); vitronectin and osteopontin antagonists (3DPharm.); combretstatin A-4 phosphate (CA4P, OxiGene, Inc.); fab fragmentα-V/β-1 integrin antagonist (Eos-200-F, Protein Design Labs); α-v/β-3integrin antagonist (Abbott Labs.); urokinase plasminogen activatorfragment (A6, Angstrom Pharm.); VEGF antagonist (AAV-PEDF, ChironCorp.); kdr tyrosine kinase inhibitor (EG-3306, Ark Therapeutics);cytochalasin E (NIH); kallikrinin-binding protein (Med. Univ. SC);combretastatin analog (MV-5-40, Tulane); pigment-epithelium derivedgrowth factor (Med. Univ. SC); pigment-epithelium derived growth factor(AdPEDF, GenVec, Inc.); plasminogen kringle (Med. Univ. SC); rapamycin;cytokine synthesis inhibitor/p38 mitogen-activated protein kinaseinhibitor (SB-220025, GlaxoSmithKline); vascular endothelial growthfactor antagonist (SP-(V5.2)C, Supratek); vascular endothelial growthfactor antagonist (SU10944, Sugen/Pfizer); vascular endothelial growthfactor antagonist (VEGF-R, Johnson & Johnson/Celltech); vascularendothelial growth factor antagonist (VEGF-TRAP, Regeneron); FGF1receptor antagonist/tyrosine kinase inhibitor (Pfizer/Sugen);endostatin, vascular endothelial growth factor antagonist (EntreMed,Inc., Rockville, Md.); bradykinin B1 receptor antagonist (B-9858,Cortech, Inc.); bactericidal/permeability-increasing protein (Neuprex®,Xoma Ltd.); protein kinase C inhibitor (Hypericin, Sigma-Aldrich, St.Louis, Mo.); ruboxistaurinn mesylate (LY-333531, Eli Lilly & Co.);polysulphonic acid derivatives (Fuji Photo Film); growth factorantagonists (TBC-2653, TBC-3685, Texas Biotech. Corp.); Tunica internalendothelial cell kinase (Amgen Inc.);

Anti-bacterials including aztreonam; cefotetan and its disodium salt;loracarbef; cefoxitin and its sodium salt; cefazolin and its sodiumsalt; cefaclor; ceftibuten and its sodium salt; ceftizoxime; ceftizoximesodium salt; cefoperazone and its sodium salt; cefuroxime and its sodiumsalt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and itssodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cefpodoxime proxetil; meropenem andits sodium salt; imipenem and its sodium salt; cilastatin and its sodiumsalt; azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof; clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof; tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;ticarcillin and its disodium salt; sulbactam and its sodium salt;moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate;trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride,sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate,or phosphate salt; minocycline and its hydrochloride, sulfate, orphosphate salt; tetracycline and its hydrochloride, sulfate, orphosphate salt; oxytetracycline and its hydrochloride, sulfate, orphosphate salt; chlortetracycline and its hydrochloride, sulfate, orphosphate salt; metronidazole; rifampin; dapsone; atovaquone; rifabutin;linezolide; polymyxin B and its hydrochloride, sulfate, or phosphatesalt; sulfacetamide and its sodium salt; minocycline; andclarithromycin;

Anti-infective Agents such as 2,4-diaminopyrimidines (e.g., brodimoprim,tetroxoprim, trimethoprim); nitrofurans (e.g., furaltadone, furazoliumchloride, nifuradene, nifuratel, nifurfoline, nifurpirinol,nifurprazine, nifurtoinol, nitrofurantoin); quinolones and analogs(e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin,fleroxacin, flumequine, gatifloxacin, grepafloxacin, lomefloxacin,miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin,trovafloxacin); sulfonamides (e.g., acetyl sulfamethoxypyrazine,benzylsulfamide, chloramine-b, chloramine-t, dichloramine t,n²-formylsulfisomidine, n⁴-β-d-glucosylsulfanilamide, mafenide,4′-(methylsulfamoyl) sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidochrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n⁴-sulfanilylsulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole); sulfones (e.g.,acedapsone, acediasulfone, acetosulfone sodium, dapsone,diathymosulfone, glucosulfone sodium, solasulfone, succisulfone,sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium,thiazolsulfone); and others (e.g., clofoctol, hexedine, methenamine,methenamine anhydromethylene-citrate, methenamine hippurate, methenaminemandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, andxibomol); moxifloxacin; and gatifloxacin;

Antifungals such as amphotericin B; pyrimethamine; flucytosine;caspofungin acetate; fluconazole; griseofulvin; terbinafin and itshydrochloride, sulfate, or phosphate salt; ketoconazole; micronazole;clotrimazole; econazole; ciclopirox; naftifine; and itraconazole;

Antimalarials such as chloroquine and its hydrochloride, sulfate orphosphate salt; hydroxychloroquine and its hydrochloride, sulfate orphosphate salt; mefloquine and its hydrochloride, sulfate, or phosphatesalt; atovaquone; proguanil and its hydrochloride, sulfate, or phosphatesalt forms;

Antituberculosis Agents such as ethambutol and its hydrochloride,sulfate, or phosphate salt forms; aminosalicylic acid; isoniazid;pyrazinamide; ethionamide;

Antivirals such as amprenavir; interferon alfa-n3; interferon alfa-2b;interferon alfacon-1; peginterferon alfa-2b; interferon alfa-2a;lamivudine; zidovudine; amadine (Symmetrel®, Endo Pharm. Inc.) and itshydrochloride, sulfate, and phosphate salts; indinavir and itshydrochloride, sulfate, or phosphate salt; ganciclovir; ganciclovirsodium salt; famciclovir; rimantadine and its hydrochloride, sulfate, orphosphate salt; saquinavir mesylate; foscarnet; zalcitabine; ritonavir;ribavirin; zanamivir; delavirdine mesylate; efavirenz; amantadine andits hydrochloride, sulfate, or phosphate salt; palivizumab; oseltamivirand its hydrochloride, sulfate, or phosphate salt; abacavir and itshydrochloride, sulfate, or phosphate salt; valganciclovir and itshydrochloride, sulfate, or phosphate salt; valacyclovir and itshydrochloride, sulfate, or phosphate salt; didanosine; nelfinavirmesylate; nevirapine; cidofovir; acyclovir; trifluridine; penciclovir;zinc oxide; zinc salicylate; zinc salts of all isomers of tocopherolhemisuccnic acid; zinc salts of straight, branched, saturated, andunsaturated chain C₂ to C₂₀ aliphatic carboxylic acids; zinc pyruvate;zinc lactate; zinc ester complexes; and zinc acetoacetonate or zincacetoacetic ester complexes;

Anti HIV/AIDS agents including stavudine, reverset (Pharmasset,Inc./Incyte Corp.), ACH-126443 (also known as Elvucitabine orBeta-L-Fd4C, Achillion Pharm., Inc.), MIV-310 (Boehringer Ingelheim),Zerit® (stavudine, d4tT, Bristol-Meyers Squibb), Ziagen® (abacavirsulfate, GlaxoSmithKline), Viread® (tenofovir disoprixil fumerate,Gilead Sci., Inc.), hivid (Roche), Emtriva (emtricitabine, Gilead Sci.,Inc.), delavirdine (Rescriptor®, Pfizer), AG-1549 (Pfizer), DPC-083(Bristol-Myers Squibb), NSC-675451 (Advanced Life Sciences), IMC-125(Tibitec), azidicarbonamide, modified tripeptideglycyl-prolyl-glycine-amide (GPG-NH2, Tripep AB), Immunitin™(Hollis-Eden Pharm.), Cytolin® (Amerimmune Pharm. Inc.), PEHRG214(Virionyx Corp.), MDX-010 (Gilead Sci., Inc.), TXU-PAP (Wayne HughesInst), Proleukin® (aldesleukin, Chiron Corp.), BAY 50-4798 (Bayer),BG-777 (Virocell), Crixivan® (Indinovir sulfate, Merck & Co., Inc.),Fuzeon® (enfuvirtide, Roche Labs. Inc.), WF-10 (Oxo Chemie), Ad5 Gagvaccine (Merck), APL400-003 and 047 (Wyeth), Remune® (OrchestraTherapeutics, Inc.), MVA-BN Nef (Bavarian Nordic), GTU® MultiHIV vaccine(FIT Biotech Oyj Plc.);

Insulins such as Novolog® (insulin aspart [rDNA origin]) and Novolin®products (Novo Nordisk Inc.); Humalog® (insulin lispro [rDNA origin]),Humalog® 75/25 and 50/50 (mixtures of insulin lispro protaminesuspension and insulin lispro), and Humulin® products (regular humaninsulin [rDNA origin], Eli Lilly & Co.); Lantus® (insulin glargine [rDNAorigin], Sanofi Aventis U.S. LLC); porcine and bovine insulins;

Glucagon-like Peptide-1 (Glp1) and analogs (for diabetes therapy andappetite suppression, cardiac protection) (see Keiffer et al., 20 EndocrRev., 876-913 (1999) such as liraglutide (Novo Nordisk Inc.); Glp1receptor stimulators such as such as Byetta® products (exenatide, andincretin mimetic, Amylin Pharm., Inc./Eli Lilly & Co.) and ZP-10(Zealand Pharma A/S); Glp-1-albumin (ConjuChem. Inc.); and Dpp-IVinhibitors (which inhibit enzyme attack on Glp-1) such as Galvus®(vildagliptin, formerly LAF237, Novartis), Januvia® sitagliptin,formerly MK-0431, Merck & Co.); saxagliptin (formerly BMS-477188,Bristol-Myers Squibb), and GSK23A (GlaxoSmithKline);

Alpha Androgenergic Agonist such as brimonidine tartrate; BetaAdrenergic Blocking Agents such as betaxolol and its hydrochloride,sulfate, or phosphate salt; levobetaxolol and its hydrochloride,sulfate, or phosphate salt; and timolol maleate;

Carbonic Anhydrase Inhibitors such as brinzolamide; dorzolamide and itsdrochloride, sulfate, or phosphate salt; and dichlorphenamid;

Mast Cell Stabilizers such as pemirolast and its potassium salt;nedocromil and its sodium salt; cromolyn and its sodium salt;

Miotics (Cholinesterase Inhibitors) such as demecarium bromide;

Prostaglandins such as bimatoprost; travoprost; and latanoprost;

Antihistamines such as olopatadine and its hydrochloride, sulfate, orphosphate salt forms; fexofenadine and its hydrochloride, sulfate, orphosphate salt; azelastine and its hydrochloride, sulfate, or phosphateforms; diphenhydramine and its hydrochloride, sulfate, or phosphateforms; and promethazine and its hydrochloride, sulfate, or phosphateforms;

Antimicrotubule Agents such as Taxoids including paclitaxel (Taxol®,Bristol-Myers Squibb); vincristine (Oncovin®, Eli Lilly & Co.) and itshydrochloride, sulfate, or phosphate salt forms; vinblastine (Velbe®,Eli Lilly & Co.) and its hydrochloride, sulfate, or phosphate salt;vinorelbine (Navelbine®, Fabre Pharm. Inc.); colchicines; docetaxel(Taxotere®, Sanofi-Aventis U.S. LLC); RPR-109881 (Sanofi-Aventis); LIT976 (Sanofi-Aventis); BMS 188797 and BMS 184476 (Bristol-Myers Squibb);DJ 927 (Daiichi Pharm. Inc.); DHA-paclitaxel (Taxoprexin®, Protarga,Inc.); Epothilones including epothiloneB such as patupilone (EPO 906,Novartis/generic), BMS 247550 and BMS-310705 (Bristol-Myers Squibb),epothilone D (KOS 862, Kosan Biosci. Inc.), and ZK EPO (Schering AG);

Antineoplastic agents such as doxorubicin and its hydrochloride,sulfate, or phosphate salt; idarubicin and its hydrochloride, sulfate,or phosphate salt; daunorubicin and its hydrochloride, sulfate, orphosphate salt; dactinomycin; epirubicin and its hydrochloride, sulfate,or phosphate salt; dacarbazine; plicamycin; mitoxantrone (Novantrone®,EMD Serono Inc.) and its hydrochloride, sulfate, or phosphate salt;valrubicin; cytarabine; nilutamide; bicalutamide; flutamide;anastrozole; exemestane; toremifene; femara; tamoxifen and tamoxifencitrate; temozolomide (Temador, Schering-Plough Corp.); gemcitabine andits hydrochloride, sulfate, or phosphate salt; topotecan and itshydrochloride, sulfate, or phosphate salt; vincristine and itshydrochloride, sulfate, or phosphate salt; liposomal vincristine (TevaPharm.); methotrexate and methotrexate sodium salt; cyclophosphamide;estramustine sodium phosphate; leuprolide and leuprolide acetate;goserelin and goserelin acetate; estradiol; ethinyl estradiol; Menest®esterified estrogens (Monarch Pharm., Inc.); Premarin® conjugatedestrogens (Wyeth Pharm. Inc.); 5-fluorouracil; bortezamib (Velcade®,Millennium Pharm., Inc.);

Antiapoptotics such as desmethyldeprenyl (DES, RetinaPharma);

Aldose Reductase Inhibitors such as GP-1447 (Grelan); NZ-314 (parabanicacid derivative, Nippon Zoki); SG-210 (Mitsubishi Pharma/Senju); andSJA-7059 (Senju);

Antihypertensives such as candesartan cilexetil (Atacand®, Takeda Pharm.Co./AstraZeneca AB); losartan (Cozaar® and Hyzaar®, Merck & Co.); andlisinopril (Zestril®, AstraZeneca AB and Prinivil®, Merck & Co.);

Antioxidants such as benfotiamine (Albert Einstein Col. Of Med./WorWagPharma); ascorbic acid and its esters; tocopherol isomers and theiresters; and raxofelast (IRFI 016, metabolized to IRFI 005, BiomedicaFoscama);

Growth Hormone Antagonists such as octreotide (Sandostatin®, Novartis);and pegvisomant (Somavert®, Pfizer);

Vitrectomy Agents such as hyaluronidase (Vitrase®, ISTA Pharm., Inc.);

Adenosine Receptor Antagonist such as A2B adenosine receptor antagonist(ATL-754, Adenosine Therapeutics, LLC);

Adenosine Deaminase Inhibitor such s pentostatin (Nipent®, SuperGenInc.);

Glycosylation Antagonists such as pyridoxamine (Pyridorin™, NephroGenexInc.);

Anti-Ageing Peptides, such as Ala-Glu-Asp-Gly (Epitalon, Geron Corp.);

Topoisomerase Inhibitors such as doxorubicin (Adriamycin®, Pfizer;Caelyx™ Schering-Plough Pharm.; Doxil®, Johnson & JohnsonPharmacia/generics); daunorubicin (DaunoXome®, Gilead Sci.); etoposide(Vepesid® and Etopophos®, Bristol-Myers Squibb); idarubicin (IdamycinPFS®, Pfizer); irinotecan (Camptosar®, Pfizer); topotecan (Hycamtin®,GlaxoSmithKline); epirubicin (Ellence®, Pfizer); and raltitrexed(Tomudex®, AstraZeneca);

Anti-metabolites such as methotrexate (generic) and its sodium salt;5-fluorouracil (Adrucil®, Teva Pharm. U.S.A.); cytarabine (Cytosar®,Upjohn Co.); fludarabine (Fludara®, Bayer HealthCare Pharm.) and itsforms as salts with acids; gemcitabine (Gemzar®, Eli Lilly & Co.);capecitabine (Xeloda®, Roche Labs. Inc.); and perillyl alcohol (POH,Endorex);

Alkylating Agents such as chlorambucil (Leukeran®, GlaxoSmithKline);cyclophosphamide (Cytoxan®, Bristol-Meyers Squibb); methchlorethanine(generic); cisplatin (Platinol®, Bristol-Meyers Squibb); carboplatin(Paraplatin®, Bristol-Myers Squibb); temozolominde (Temodar®, ScheringCorp.) and oxaliplatin (Eloxatin® Sanofi-Synthelabo, Inc.);

Anti-androgens such as flutamide (Eulexin®, Schering-Plough); nilutamide(Nilandron®, Sanofi-Aventis); bicalutamide (Casodex®, AstraZeneca);

Anti-oestrogens such as tamoxifen (Nolvadex®, AstraZeneca); toremofine(Fareston, Orion/Shire); fulvestrant (Faslodex®, AstraZeneca);arzoxifene (Eli Lilly & Co.); anastrozole (Arimidex™, AstraZeneca);letrozole (Femerar™, Novartis); formestan (Lentaron®, Novartis);exemestane (Aromasin®, Pfizer); goserelin acetate (Zoladex®,AstraZeneca); lasoxifene (Pfizer); ERA-923 (Ligand Pharm. Inc./Wyeth);DCP 974 (DuPont/Bristol-Myers Squibb); ZK 235253, ZK 911703, and ZK230211 (Schering AG);

Oncogene Activation Inhibitors, including for example, Bcr-Abl KinaseInhibition such as imatinib mesylate (Gleevec™, Novartis); Her2Inhibition such as trastuzumab (Herceptin®, Genentech, Inc.); MDX 210(Medarex, Inc.); E1A (Targeted Genetics Corp.); ME 103 and ME 104(Pharmexa); rhuMAb-2C4 (Omnitarg, Genentech, Inc.); C1-1033 (Pfizer);PK1 166 (Novartis Pharma AG); GW572016 (GlaxoSmithKline); EGFrInhibitors such as cetuximab (Erbitux™, Imclone Sys. Inc.); EGFrTyrosine Kinase Inhibitors such as gefitinib (Iressa®, formerly ZD 1839,AstraZeneca); erlotinib (Tarceva, Genentech, Inc./OSI Pharm., Inc.);ABX-EGF (Abgenix/Amgen); erbB receptor inhibitor (C1-1033, Pfizer); EMD72000 (Merck KgaA); lapatinib (GW572016, GlaxoSmithKline); EKB 569(Wyeth); PKI 166 (Novartis); and BIBX 1382 (Boehringer Ingleheim);Farnesyl Transferase Inhibitors such as tipifamib (Zarnestra®, Johnson &Johnson); lonafarnib (Sarasar™, Schering-Plough); BMS-214,662(Bristol-Myers Squibb); AZ3409 (AstraZeneca); CP-609754 and CP-663427(OSI Pharmaceuticals/Pfizer); Arglabin (NuOncology Labs Inc.);RPR-130401 (Aventis Pharm.); A-176120 (Abbott Labs.); BIM 46228(Biomeasure, Inc.); LB 42708 and LB 42909 (LG Chem, Ltd.); PD 169451(Pfizer); and SCH226374 (Schering-Plough); Bcl-2 Inhibitors such asBCL-X (Isis Pharm., Inc.); ODN 2009 (Novartis Pharm.); GX 011 (Gemin XBiotech. Inc.); and TAS 301 (Taiho Pharm. Co.); Cyclin Dependent KinaseInhibitors such as flavopiridol (generic, Aventis Oncol.); CYC202(R-roscovitine, Cyclacel Ltd.); BMS 387032, BMS 239091 and BMS 250904(Bristol-Myers Squibb); CGP 79807 (Novartis Pharm.); NP102 (NicholasPiramal India Ltd.); and NU 6102 (AstraZeneca); Protein Kinase CInhibitors such as Affinitac™ (Isis Pharm., Inc./Eli Lilly & Co.);midostaurin (PKC 412, Novartis/generic); bryostatin (Aphios Corp.); KW2401 (Kyowa Hakko Kogyo/Keryx Biopharm.); LY 317615 (Eli Lilly & Co.);perifosine (Keryx Biopharm); and balanol (SPC 100840, Sphinx Pharm./EliLilly & Co.)

Telomerase Inhibitors such as GRN163 (Geron Corp./Kyowa Hakko Kogyo) andG4T 405 (Aventis);

Antibody Therapy including Herceptin® (trastuzumab Genentech, Inc.);MDX-H210 (Medarex, Inc.); SGN-15 (Seattle Genetics); H11 (Viventia);Therex (Antisoma); rituximan (Rituxan®, Genentech); Campath (ILEXOncology/Millennium/Shering); Mylotarg (Celltech/Wyeth); Zevalin (IDECPharmaceuticals/Schering); tositumomab (Bexxar, Corixa/SmithKlineBeecham/Coulter); epratuzumab (Lymphocide, Immunomedics/Amgen); Oncolym(Techniclone/Schering AG); Mab Hu1D10 antibody (Protein DesignLaboratories); ABX-EGF (Abgenix); infleximab (Remicade®, Centocor) andetanercept (Enbrel, Wyeth-Ayerst);

Antisense Oligonucleotides such as Affinitac (Isis Pharmaceuticals/EliLilly & Co.); and Genasence (Genta/Aventis);

Fusion Proteins such as denileukin diftitox (Ontak, Ligand);

Luteineizing Hormone Releasing Hormone (LHRH) Agonists aka GonadotropinReleasing Hormone (GnRH) Agonists such as goserelin (Zoladex,AstraZeneca); leuporelin (Lupron, Abbott/Takeda); leuporelin acetateimplant (Viadur, ALZA/Bayer and Atigrel/Eligard,Atrix/Sanofi-Synthelabo); and triptorelin (Trelstar, Pharmaceuticals);

Tyrosine Kinase Inhibitors/Epidermal Growth Factor Receptor Inhibitorssuch as gefitinib (Iressa, AstraZeneca, ZD 1839); trastuzumab(Herceptin, Genentech); erlotinib (Tarceva, OSI Pharmaceuticals, OSI774); cetuximab (Erbitux, Imclone Systems, IMC 225); and pertuzumab(Omnitarg, Genentech, 2C4);

Ribonucleotide Reductase Inhibitors such as gallium maltolate (Titan);

Cytotoxins such as Irofulven (MGI 114, MGI Pharma);

IL2 Therapeutics such as Leuvectin (Vical);

Neurotensin Antagonist such as SR 48692 (Sanofi-Synthelabo);

Peripheral Sigma Ligands such as SR 31747 (Sanofi-Synthelabo);

Endothelin ETA/Receptor Antagonists such as YM-598 (Yamanouchi); andatrasentan (ABT-627, Abbott);

Antihyperglycemics such as metformin (Glucophage, Bristol-Myers Squibb)and its hydrochloride, sulfate, phosphate salts; and miglitol (Glyset,Pharmacia/Upjohn);

Anti-glaucoma Agents such as dorzolamide (Cosopt, Merck); timolol;betaxolol and its hydrochloride, sulfate, phosphate salts; atenolol; andchlorthalidone;

Anti-(Chromatin Modifying Enzymes) such as suberoylanilide hyroxaxamicacid (Aton/Merck);

Agents for Obesity Management, such as glucagon-like-peptides,phendimettrazine and its tartrate, hydrochloride, sulfate, phosphatesalts; methamphetamine and its hydrochloride, sulfate, phosphate salts;and sibutramine (Meridia, Abbott) and its hydrochloride, sulfate,phosphate salts;

Treatments for Anemia such as epoetin alpha (Epogen, Amgen); epoetinalpha (Eprex/Procrit, Johnson & Johnson); epoetin alpha (ESPO, Sankyoand Kirin); and darbepoetin alpha (Aranesp, Amgen); epoetin beta(NeoRecormon, Roche); epoetin beta (Epogen, Chugai); GA-EPO (Dynepo,TKT/Aventis); epoetin omega (Elanex/Baxter); R 744 (Roche); andthrombopoetin (Genetech/Pharmacia);

Treatments for Emesis such as promethazine (Phenergan, Wyeth);prochlorperazine; metoclopramide (Reglan, Wyeth); droperidol;haloperidol; dronabinol (Roxane); ondasetron (Zofran, GlaxoSmithKline);ganisetron (Kytril, Roche); dolasetron (Anzemet, Aventis); indisetron(NN-3389, Nisshin Flour/Kyorin); aprepitant (MK-869, Merck);palonosetron (Roche/Helsinn/MGI Pharma); lerisetron (FAES); nolpitantium(SR 14033, Sanofi-Synthelabo); R1124 (Roche); VML 670 (Vernalis, EliLilly & Co.); and CP 122721 (Pfizer);

Neutropaenia Treatments such as filgrastim (Neupogen, Amgen); leukine(Immunex/Schering AG); filgrastim-PEG (Neulasta, Amgen); PT 100 (PointTherapeutics); and SB 251353 (GlaxoSmithKline);

Tumor-induced Hypercalcaemia Treatments such as Bonviva(GlaxoSmithKline); ibandronate (Bondronat, Roche); pamidronate (Aredia,Novartis); zolendronate (Zometa, Novartis); clodronate (Bonefos,generic); incadronate (Bisphonal, Yamanouchi); calcitonin(Miacalcitonon, Novartis); minodronate (YM 529/Ono 5920,Yamanouchi/Ono); and anti-PTHrP (CAL, Chugai);

Blood Anticoagulants such as Argathroban (GlaxoSmithKline); warfarin(Coumadin, duPont); heparin (Fragmin, Pharmacia/Upjohn); heparin(Wyeth-Ayerst); tirofiban (Aggrastat, Merck) and its hydrochloride,sulfate, phosphate salts; dipyridamole (Aggrenox, Boehringer Ingelheim);anagrelide (Agrylin, Shire US) and its hydrochloride, sulfate, phosphatesalts; epoprostenol (Flolan, GlaxoSmithKline) and its hydrochloride,sulfate, phosphate salts; eptifibatide (Integrilin, COR Therapeutics);clopidogrel (Plavix, Bristol-Myers Squibb) and its hydrochloride,sulfate, or phosphate salts; cilostazol (Pletal, Pharmacia/Upjohn);abciximab (Reopro, Eli Lilly & Co.); and ticlopidine (Ticlid, Roche);

Immunosuppressive Agents such as sirolimus (rapamycin, Rapamune®,Wyeth-Ayerst); tacrolimus (Prograf, FK506); and cyclosporins;

Tissue Repair Agents such as Chrysalin (TRAP-508, Orthologic-ChrysalisBiotechnology);

Anti-psoriasis Agents such as anthralin; vitamin D3; cyclosporine;methotrexate; etretinate, salicylic acid; isotretinoin; andcorticosteroids;

Anti-acne Agents such as retinoic acid; benzoyl peroxide;sulfur-resorcinol; azelaic acid; clendamycin; erythromycin;isotretinoin; tetracycline; minocycline;

Anti-skin parasitic Agents such as permethrin and thiabendazole;

Treatments for Alopecia such as minoxidil and finasteride;

Contraceptives such as medroxyprogesterone; norgestimol; desogestrel;levonorgestrel; norethindrone; norethindrone; ethynodiol; and ethinylestradiol; Treatments for Smoking Cessation including nicotine;bupropion; and buspirone;

Treatments for Erectile Disfunction such as alprostadil; and Sildenafil;

DNA-alkyltranferase Agonist including temozolomide;

Metalloproteinase Inhibitor such as marimastat;

Agents for management of wrinkles, bladder, prostatic and pelvic floordisorders such as botulinum toxin;

Agents for management of uterine fibroids such as pirfenidone, humaninterferin-alpha, GnRH antagonists, Redoxifene, estrogen-receptormodulators;

Transferrin Agonist including TransMID™ (modified diphtheria toxinconjugated to transferrin, Tf-CRM107, Xenova Group Ltd.);

Interleukin-13 Receptor Agonist such as IL-13-PE38QQR (Neopharm);

Nucleic acids such as small interfering RNAs (siRNA) or RNA interference(RNAi), particularly, for example siRNAs that interfere with VEGFexpression;

and Psychotherapeutic Agents including Anti-anxiety drugs such aschlordiazepoxide; diazepam; chlorazepate; flurazepam; halazepam;prazepam; clorazepam; quarzepam; alprazolam; lorazepam; orazepam;temazepam; and triazolam; and Anti-psychotic drugs such aschlorpromazine; thioridazine; mesoridazine; trifluorperazine;fluphenazine; loxapine; molindone; thiothixene; haloperidol; pimozide;and clozapine.

Those of ordinary skill in the art will appreciate that any of theforegoing disclosed active agents may be used in combination or mixturein the pharmaceutical formulations of the present invention. Suchmixtures or combinations may be delivered in a single formulation, ormay be embodied as different formulations delivered eithersimultaneously or a distinct time points to affect the desiredtherapeutic outcome. Additionally, many of the foregoing agents may havemore than one activity or have more than one therapeutic use, hence theparticular category to which they have been ascribed herein is notlimiting in any way. Similarly, various biodegradable, biocompatibleexcipients may be used in combination or in mixtures in single ormultiple formulations as required for a particular indication. Thesemixtures and combinations of active agents and excipients may bedetermined without undue experimentation by those of ordinary skill inthe art in light of this disclosure.

The formulations of the present invention may be sterilized for use bymethods known to those of ordinary skill in the art. Autoclaving ande-beam have been used in informal studies of several embodiments andhave not appeared to have significant impact. Similarly, informalstability studies indicate acceptable stability of several embodiments.Additionally, reproducibility between aliquots and lots is very good,with a standard deviation of less than five percent or better. Hence,standard pharmaceutical manufacturing techniques are readily applied tothe technologies described herein.

An example embodiment of the present invention comprises the activeagent dexamethasone and the excipient benzyl benzoate. Dexamethasone isa glucocorticoid and typically used in the form of the acetate ordisodium phosphate ester. Glucocorticoids are adrenocortical steroidssuppressing the inflammatory response to a variety of agents that can beof mechanical, chemical or immunological nature. Administration ofdexamethasone can be topical, periocular, systemic (oral) andintravitreal. Doses vary depending on the condition treated and on theindividual patient response. In ophthalmology, dexamethasone sodiumphosphate (Decadron®, Merck & Co.) as a 0.1% solution has been widelyused since its introduction in 1957. The ophthalmic dose depends on thecondition treated. For control of anterior chamber inflammation, the-topical dose is usually 1 drop, 4 times a day for up to a monthfollowing surgery (around 0.5 mg per day). For control of posteriorsegment inflammation, periocular injections of 4 mg of dexamethasone, ordaily oral administration of 0.75 mg to 9 mg of dexamethasone in divideddoses are not uncommon. Intravitreal injections of 0.4 mg ofdexamethasone have been administered in conjunction with antibiotics forthe treatment of endophthalmitis.

Regarding benzyl benzoate (CAS120-51-4, FW 212.3), previously the oraladministration of benzyl benzoate was claimed to be efficacious in thetreatment of intestinal, bronchial, and urinary ailments, but its usehas been superseded by more effective drugs. Presently, it is topicallyapplied as a treatment for scabies and pediculosis. Goodman & Gilman'sTHE PHARMACOLOGICAL BASIS OF THERAPEUTICS 1630 (6th ed., 1980); FDAapproval, Fed Reg. 310.545(a)(25)(i). Benzyl benzoate is approved inminor amounts in foods as a flavoring (FDA, Title 21, vol. 3, ch I,subch B, part 172(F), § 172.515), and as a component in solvents forinjectable drug formulations (e.g., Faslodex® and Delestrogen®).

Benzyl benzoate is a relatively nontoxic liquid which when appliedtopically in the eye results in no damage. Grant, TOXICOLOGY OF THE EYE185 (2d ed., 1974). Its oral LD₅₀ in humans is estimated to be 0.5g/kg-5.0 g/kg. Gosselin et al., II CLIN TOX OF COMMERCIAL PROD. 137 (4thed., 1976). In vivo, benzyl benzoate is rapidly hydrolyzed to benzoicacid and benzyl alcohol. The benzyl alcohol is subsequently oxidized tobenzoic acid, which is then conjugated with glucuronic acid and excretedin the urine as benzoylglucuronic acid. To a lesser extent, benzoic acidis conjugated with glycine and excreted in the urine as hippuric acid.HANDBOOK OF PESTCIDE TOXICOLOGY 1506 (Hayes & Laws, eds., 1991).

Dexamethasone, when mixed with benzyl benzoate, forms a uniformsuspension. A dexamethasone/benzyl benzoate formulation of 25% is easilysyringeable. When the suspension is injected slowly into the posteriorsegment of the eye, for example, a uniform spherical deposit (reservoir)is formed in the vitreous body. The reservoir maintains its integrityand in vivo “breakage” has not been observed opthalmoscopically.Dexamethasone is then released slowly into the vitreous humor of theposterior segment. Dexamethasone and benzyl benzoate are eventuallymetabolized to byproducts that are excreted in the urine.

Similarly, triamcinolone acetonide (TA) in benzyl benzoate forms asyringeable suspension that retains its integrity and in vivo. In rabbitstudies involving intraocular injection of TA/benzyl benzoateformulations, described below, near zero-order release of TA has beenobserved in vivo for more than one year. Smaller doses result inmore-rapid release profiles, such that the TA is released over asix-month period. Both Dex and TA formulations may be useful in treatingthe eye following cataract surgery or replacement.

Further regarding cataract surgery and other treatments or diseases ofthe eye, an aspect of the invention provides for a compositioncomprising an active agent and the LSBB excipient useful for thetreatment of iris neovascularization from cataract surgery, macularedema in central retinal vein occlusion, cellular transplantation (as inretinal pigment cell transplantation), cystoid macular edema,psaudophakic cystoid macular edema, diabetic macular edema,pre-phthisical ocular hypotomy, proliferative vitreoretinopathy,proliferative diabetic retinopathy, exudative age-related maculardegeneration, extensive exudative retinal detachment (Coat's disease),diabetic retinal edema, diffuse diabetic macular edema, ischemicopthalmopathy, chronic focal immunologic corneal graft reaction,neovascular glaucoma, pars plana vitrectomy (for proliferative diabeticretinopathy), pars plana vitrectomy for proliferative vitreoretinopathy,sympathetic ophthalmia, intermediate uveitis, chronic uveitis,intraocular infection such as endophthalmitis, and/or Irvine-Gasssyndrome.

Another embodiment of the invention provides formulations and uses ofthe tocopherols and/or tocotrienols and their esters with insulins forthe transdermal delivery of the insulins in the management of diabetes.Tocopherols and/or the tocotrienols and their esters possess outstandingcapabilities to carry therapeutic agents, especially moderate molecularweight proteins such as the insulins, through the skin into the body.Indeed, it is contemplated that wide variety of other therapeutic agents(such as steroids, NSAIDs, antibiotics, hormones, growth factors,anti-cancer agents, etc.) may be available for effective transdermaldelivery formulations with the tocopherols and/or tocotrienols and theiresters.

The advantages to bypassing oral drug delivery that allow the enzymatictransformations of the liver and the digestive processes of the gut (andalso engender gastric distresses) have inspired research to findalternative methods. A prime example is insulin therapy for diabetes.Several tutorials and reviews of the present state of insulin therapiesare: Owens, 1 Nature Reviews/Drug Discovery 529-540 (2002); Cefalu, 113(6A) Am J Med 25S-35S (2002); Nourparvar et al., 25 (2) Trends PharmacolSci, 86-91 (2004). Avoidance of daily multiple painful subcutaneousinjections has led to alternative routes such as buccal/sublingual,rectal, intranasal, pulmonary, and transdermal. Yet no completelyacceptable alternatives to injection have been established. Mostpromising are pulmonary systems (Exubera®, insulin human [rDNA origin])Inhalation Powder, Pfizer; AERx® iDMS, liquid aerosol insulinformulation, Novo Nordisk) and as disclosed here novel transdermaldelivery formulations involving the tocopherols and/or tocotrienols andtheir esters as penetrating vehicles for therapeutic agents.

The desirability of simple and painless transdermal delivery of insulinand other therapeutic agents has inspired a number of transdermalapproaches (iontophoresis [electrical charge]; phonophoresis(ultrasound); photoenhancement (pulsed laser); heat; lipid vesicles; andpenetrating agents [DMSO, NMP, etc.]) over the years with incompleteresults. Transdermal delivery is considered to be hindered by the skin'srelatively impermeability to large hydrophilic polypeptides such asinsulin. The present invention, however, provides effective levels ofinsulin delivered in a sustained release fashion into the bloodstreamwhen applied as intimate mixtures with α-tocopheryl acetate onto theskin. In a mouse model, effective levels of insulin were delivered in asustained release fashion into the bloodstream of a mouse when appliedas intimate mixtures with α-tocopheryl acetate onto the mouse skin.

Because tocopherols have long been ingredients in sunscreen and cosmeticformulations, there are numerous references in the literature to thetocopherols being applied to the skin and demonstrations of theirmigrating through the skin. See e.g., Zondlo, 21 (Suppl 3) Int'l JToxicol, 51-116 (2002). These reports show the ease and safety withwhich the tocopherols can penetrate skin, but none disclose any use ofthe tocopherols as penetration enhancers or carriers of therapeuticagents through the skin into the body. Indeed, a recent review of 102chemical penetration enhancers for transdermal drug delivery did notmention the tocopherols or tocotrienols. Karande et al., 102 (13) ProcNatl Acad Sci USA, 4688-93 (2005).

Tocopherol formulations that allow the facile and effective transport oftherapeutic agents through the skin into the body may employ d, 1, andd1 isomers of alpha, beta, gamma and delta tocopherols and their esters(formates, acetates, propionates, C₄ to C₂₀ straight and branched chainaliphatic acid esters, maleates, malonates, fumarates, succinates,ascorbates, and nicotinates); d, 1, and d1 isomers of alpha, beta,gamma, and delta tocotrienols and their esters (formates, acetates,propionates, C₄ to C₂₀ straight and branched chain aliphatic acidesters, maleates, malonates, fumarates, succinates, ascorbates, andnicotinates).

Another embodiment of the present invention, further related to thetocopherols, provides to formulations of 2-acetyloxy benzoic acid andits aliphatic esters with tocopherols and tocotrienols and licoriceextracts. In particular, this aspect provides for injectable, ingestableor topical formulations employing the tocopherols and/or tocotrienolsand/or licorice extracts with 2-acetyloxybenzoic acid (2-ABA) andcertain of its aliphatic esters, that allow all the well-known medicinalbenefits of 2-ABA and its aliphatic esters while substantially avoidingthe gastric toxicities normally associated with the ingestion of 2-ABAitself.

Unlike the more recently developed specific COX-2 inhibitingnonsteroidal anti-inflammatories such as celecoxib (Celebrex®, Pfizer),rofecoxib (Vioxx®, Merck), and the like, there is the confidence thatdecades of pharmaceutical experience with 2-ABA have well defined itsbenefits and disadvantages. The full benefits and problems of thespecific COX-2 inhibitors are still being discovered. In the case of the“traditional” NSAIDs such as 2-ABA, ibuprofen, naproxen, ketoprofen,diclofenac, indimethacin, etc., evidence accumulates on the damage theydo to the stomach and small bowel. Although the specific COX-2inhibitors have demonstrated lower gastrointestinal problems than 2-ABA,serious cardiovascular problems associated with specific COX-2inhibitors are surfacing. As for 2-ABA, its general analgesicanti-inflammatory benefits are legendary; and as the chemistries of bothof its COX-1 and COX-2 inhibitions are revealed the cardioprotectiveproperties associated with its COX-1 inhibition are in striking contrastto the cardiovascular safety problems of the COX-2 only inhibitors. Thereason for 2-ABA's gastrointestinal toxicity has been ascribed to itsCOX-1 inhibition. And indeed the lower order of gastrointestinalproblems of celecoxib, rofecoxib, and the like is seen to be due totheir COX-2 only inhibition. But, interestingly, the normal intestinalappearances in the COX-1 knockout animals point to more subtle reasonsfor 2-ABA's gastrointestinal toxicity, in which the concomitantinhibition of both COX-1 and COX-2 enzymes may be the problem.

Whatever the mechanisms for 2-ABA's gastrointestinal toxicity, the welldemonstrated benefits of 2-ABA in other areas of the body are incentivesto seek ways to get the molecule past the gut without damage. Of courseinjection or topical applications avoid the gut, but the major mode ofcurrent administration remains ingestion. Three distinctly differentmethods of lowering the gut irritation of ingested 2-ABA have beenreported. The first, and most successful, is the discovery in studies inrats and pigs by Rainsford and Whitehouse reported in 1980 (10 (5)Agents & Actions, 451-56), that the methyl, ethyl, and phenyl esters of2-ABA elicit practically no gastric ulcerogenic activity and yet stillhave nearly all the anti-inflammatory properties of 2-ABA. Surprisingly,the investigation of oral administrations of the esters of 2-ABA has notbeen pursued further. Topical applications of 2-ABA esters for acnecontrol, sunscreen, and placating insect bites have been reported. SeeU.S. Pat. No. 4,244,948, U.S. Pat. No. 4,454,122, U.S. Pat. No.3,119,739. The second method of reducing 2-ABA gastric distressrecommends diets rich in tocopherols and/or tocotrienols, resulting inabout a 30% to 40% reduction in lesion formation which is not asextensive as that provided by 2-ABA esters. See e.g., Jaarin et al., 13(Suppl) Asia Pac J Clin Nutr, 5170 (2004); Nafeeza et al., 11 (4) AsiaPac J Clin Nutr 309-13 (2002); Sugimoto et al., 45 (3) Dig Dis Sci,599-605 (2000); Stickel et al, 66 (5) Am J Clin Nutr 1218-23 (1997). Thethird method of reducing gastric stress is by the concomitant oraladministration of licorice extract (glycyrrhizin) with 2-ABA. Rainsford& Whitehouse, 21 Life Sciences 371-78 (1977); Dehpour et al., 46 J PharmPharmacol 148-49 (1994). This gave 66% to 80% reduction in ulcerationcompared to 2-ABA alone. Formulations combining 2-ABA or its esters, thetocopherols (or their acetates) and/or tocotrienols (or their acetates),and licorice extracts in combination have not been tried.

Treatment of inflammatory conditions of the eye or joints by directinjection avoids gastric distress and the inefficient systemic exposureof the ingestion route. Ingestion in humans of the commonly prescribedosages of 2-ABA (0.650-1.3 g) leads to combined 2-ABA/2-hydroxy benzoicacid (2-HBA) levels in the plasma of about 20-100 μg/ml. Kralinger etal., 35 Ophthalmic Res 107 (2003). Studies in rabbit eyes indicate thatat these plasma levels the concentration of 2-ABA/2-HBA in the vitreousis in the range of 5-10 μg/ml. The 2-ABA level is much lower than 2-HBAsince within 30 minutes in the plasma about 97% of the 2-ABA ishydrolyzed to 2-HBA. Once remaining 2-ABA reaches the vitreous its rateof hydrolysis in that environment is greatly reduced. There an initiallevel of 4 μg/ml is halved in 1.5-2 hours. the half-life of 2-HBA is notwell defined since its initial concentration is increased by theconversion of 2-ABA to 2-HBA; but the half life is probably twice thatof 2-ABA. Valeri et al., 6 (3) Lens & Eye Toxicity Res 465-75 (1989).This highlights another advantage of direct injection over oral(systemic) administration: injection avoids the substantial loss of theacetyl group in the hydrolysis of 2-ABA before it reaches its target. Ithas been shown that the major method of 2-ABA's anti-inflammatory actionis its ability deactivate the COX-1 and COC-2 enzymes by irreversiblyinserting its acetyl group into these enzymes. Roth & Majerus, 56 J ClinInvest 624-32 (1975). The ID₅₀ for this reaction in the eye has beendetermined to be in the range of 0.9-9.0 μg/ml. Higgs et al, 6 (Suppl)Agents & Actions 167-75 (1979). Kahler et al., 262 (3) Eur J Pharmacol261-269 (1994).

One example of an injectable sustained release (ISR) 2-ABA formulationin the eye is the injection of a 1.0 ml tamponade of silicone oilcontaining 1.67 mg into rabbit eye vitreous chamber. Only 2-HBA wasmeasured in the study, which observed an initial burst of 640 μg/mlwithin 6 hours. 2-HBA decreased to 20 μg/ml in 20 hours and 5 μg/mlafter 120 hours. Kralinger et al., 21 (5) Retina 513-20 (2001). The useof the ethyl ester of 2-ABA in ISR formulations should give longer halflives (longer sustained deliveries) than 2-ABA since the ester is morehydrophobic. Also, the incorporation of 2-ABA esters or 2-ABA intohydrophobic excipients such as the tocopherols (or their acetates) orthe tocotrienols (or their acetates) should lead to longer sustaineddeliveries.

A study of the distribution of 2-ABA and 2-HBA in the blood and synovialfluid (human knee) from ingested 650 mg doses of 2-ABA showed themaximum plasma levels of 3.3 μg/ml 2-ABA in 7.7 minutes and 23 μg/ml2-HBA in 10.9 minutes. Maximum synovial fluid levels were 2.5 μg/ml2-ABA in 19.4 minutes and 14.5 μg/ml 2-HBA in 21.9 minutes. Soren, 6 (1)Scand J Rheumatol 17-22 (1977). The 2-ABA was gone in the blood in 75minutes and gone in the synovial fluid in 2.3 to 2.4 hours. A study ofintra-articular injections of 20 μg/ml 2-ABA in the 33 ml of synovialfluid in the adult human knee also revealed that the average half lifeof combined 2-ABA/2-HBA was 2.4 hours. Owen et al., 38 Brit. J. Clin.Pharma. 347-55 (1994); Wallis et al., 28 Arthritis Rheum 441-49 (1985).

In addition to the references noted above relating to anti-inflammationtherapies involving topical applications of 2-ABA ester formulations,there are the references referring to 2-ABA esters (U.S. Pat. No.3,119,739, U.S. Patent Application Pub. No. 2002-0013300) or 2-ABA (U.S.Pat. No. 4,126,681) as analgesics for skin irritations and woundhealing. Other reports, however, reveal poor results with topicallyapplied 2-ABA to relieve pain from insect bites (Balit et al., 41 (6)Toxicol Clin Toxicol 801-08 (2003)) or allergic reactions (Thomsen etal., 82 Acta Derm Venereal 30-35 (2002)). Better results were found ondermal applications of chloroform solutions of 2-ABA (Kochar et al., 47(4) J Assoc Physicians India 337-40 (1999)) or slurries of 2-ABA in acommercial skin moisturizer (Balakrishnan et al., 40 (8) Int J Dermatol535-38 (2002)) to alleviate the pain of acute herpetic neuralgia. It isimportant to note that most of these reported formulations containedwater. Thus, unless these formulations were used immediately after theirpreparation it is very likely significant hydrolysis of the 2-ABAs ortheir esters removed the acetyl group to give the less potent 2-HBAderivatives. There is the need for non-aqueous or non-alcoholicpenetrating excipients in topical 2-ABA and 2-ABA ester formulations foruseful shelf life.

Hence, in an embodiment of the invention the components used in theformulations are selected from the following two groups:

-   -   Group I: 2-acetyloxy benzoic acid, methyl 2-acetyloxy benzoate,        ethyl 2-acetyloxy benzoate, n-propyl 2-actyloxy benzoate,        isopropyl 2-acetyloxy benzoate, n-butyl 2-acetyloxy benzoate,        isobutyl 2-acetyloxy benzoate.    -   Group II: d, 1 and d1 isomers of alpha, beta, gamma and delta        tocopherols and their acetate esters; d, 1 and d1 isomers of        alpha, beta, gamma, and delta cotrienols and their acetate        esters; all along with licorice extracts or deglycyrrhized        licorice extracts.

Thus, one aspect of this invention involves novel mixtures of compoundsselected from group I with compounds selected from group II to giveformulations for oral administration having essentially all thebeneficial therapeutic properties of 2-ABA but with much less to none ofthe gastric stress associated with 2-ABA. These novel formulations foringestion have the general compositions of 350 pts/wt 2-ABA or 400 to500 pts/wt of 2-ABA esters mixed with 40 to 400 pts/wt tocopherols ortheir acetates plus 35 to 110 pts/wt tocotrienols or their acetates plus400 to 1400 pts/wt licorice extract or degglycerrhized licorice extract.A convenient source containing mixture of tocopherols and tocotrienolsis either palm seed oil extract (Carotech Inc. among many suppliers) orrice bran oil extract (Eastman Chemicals, among many other suppliers).There is some evidence that the palm seed source is preferred because ithas a higher delta tocotrienol content. Theriault et al., 32 (5) ClinBiochem 309-19 (1999); Yap et al., 53 (1) J Pharm Pharmacol 67-71(2001).

An example, but non-limiting, formulation would be: 350 mg 2-ABA (or 400mg ethyl 2-ABA); 200 mg tocopherol/tocotrienol (palm seed oil extract);and 125 mg licorice extract. Such a formulation might be convenientlycontained in a gel capsule with one to eight capsules/day being ingestedas needed to alleviate inflammatory conditions throughout the human oranimal body.

Another aspect of this invention involves novel sustained releasemixtures of 2-ABA or 2-ABA esters with tocopherol or tocopherol acetatefor intra-ocular or intra-articular injections as therapies forinflammatory conditions of the eye or joints of animals or humans. Thegeneral range of amounts of these components in the formulations is 5 to95 pts/wt 2-ABA esters or micronized 2-ABA and 95 pts/wt to 5 pts/wttocopherol or its acetate. An example, but non-limiting, formulation is250 pts/wt ethyl 2-ABA or micronized 2-ABA; 400 pts/wt α-d1 ord-tocopherol acetate. This formulation is amenable to injection through20 gauge to 30 gauge needles in 10 mg to 100 mg aliquots into thevitreous chamber of the eye to provide sustained release of therapeuticlevels of 2-ABA or its ester for periods of ten days to one year.Similarly, 10 mg to 3000 mg of these formulations may be injected intothe synovial chambers of human or animal joints to provideanti-inflammatory therapy for periods of ten days to one year.

A further aspect of this invention involves novel formulations of 5pts/wt to 95 pts/wt 2-ABA or its esters with 95 pts/wt to 5 pts/wttocopherols, tocopherol acetates and/or tocotrienols, tocotrienolacetates for the topical applications to penetrate the skin of humans oranimals to alleviate inflammation and pain in the skin or joints. Again,a convenient source of both the tocopherols and tocotrienols would bepalm seed oil or rice bran oil extracts. A specific non-limitingformulation would be: 60 pts/wt ethyl 2-ABA or micronized 2-ABA; 40pts/wt palm seed oil extract.

Another aspect of the present invention provides formulations useful intreating brain tumors. The incidence of brain tumors is continuing toincrease and becomes more marked as the population ages. Thus, forexample the average incidence is 1.8/100,000 people 15-24 years of agebut about 18.4/100,000 of those 65-79 years of age. The age peak isbetween 55 and 73 years, although increasing numbers of young patientswith glioblastomas have been recorded in recent years. The estimatednumber of people living in the US with a diagnosis of primary brain andcentral nervous system tumor is about 360,000. The annual incidence of aprimary brain tumor in the U.S. is about 18,500 people, of whom most diewithin the first year after discovery. Despite surgery, irradiation, orpresent chemotherapy regimens, patients survive on average for onlyeleven months. The tumors, by then, become large enough to crush vitalportions of the brain.

The tumors which occur most commonly originate from astrocytes,ependymocytes and oligodendrocytes. The prognosis of brain tumors ispoor. Malignant gliomas account for 42% of all primary brain/CNS tumors,and of these in turn glioblastoma multiforme (GBM) and anaplasticastrocytoma, which together account for about 80% of all malignantgliomas, and have the poorest prognosis. The GBM is the subject of muchresearch because it is the most common and potentially destructive braintumor. While many tumors contain a mixture of cell types, GBM is themost mixed of brain tumors. It is this characteristic that makes itdifficult to treat. While one cell type may be responsive to a treatmentand dies, other types are waiting to take over. Additionally, often onlypartial tumor resection is possible, leaving remaining and dislodgedcancer cells that can stray throughout the brain. The histologicdistribution of primary brain and CNS gliomas is: glioblastoma 50.5%,ogliodendrogliomas 9.5%, ependymomas 4.9%, all other gliomas 9.7%,anaplastic astrocytomas 8.2%, pilocytic astrocytomas 4.7%, diffuseastrocytomas 1.8%, all other astrocytomas 9.3%.

The currently available nonsurgical therapeutic options, irradiation andsystemic chemotherapy, are all associated with adverse reactions, someof which are severe, which represent limiting factors for anincreasingly aging population afflicted with other multiple pathologies.The main problem is the fact that recurrence of these tumors isunavoidable even with, or despite, the use of present day aggressivesurgical, radiation, and chemotherapy regimens.

Surgical removal of a tumor though resulting in initial relief ofpressure seldom is able to capture all of the malignancy. It has beenreported that the recurrence rate and increased growth rate is near 100%after resectioning in GMB atients. Recently it has been demonstratedexperimentally using MRI imaging that there is an accelerated growth inbrain tumor volume following incomplete surgical resectioning. It isvery likely that tissue injury promotes cancer growth by altering themicro-environment and provides a more permissive field for tumorexpansion and invasion. Local outpouring of inflammatory cytokines andvascular endothelial growth factors are likely contributors to thisenvironment. In addition to this acceleration of the proliferation ofthe remaining malignant tissue there is often significant collateraldamage to healthy tissue, troublesome bleeding and edema.

Irradiation procedures also lead to considerable collateral damage. Inaddition to initial edema there are delayed reactions over weeks tomonths manifested by neuropsycho-logical disorders, dementia, and/oratrophy of the cerebral cortex among others.

The chemical therapeutic regimens which with few exceptions involvesystemic administrations with their collateral damage to other areas ofthe body, also must contend with the blood-brain barrier to penetrationof the drug to the desired site. In principle then, primary brain tumorsare categorized as tumors for which even now there are no effective,curative therapeutic approaches.

The novel biocompatible, biodegradable sustained release formulationsrevealed in the present invention are either syringeable liquids,mechanically cohesive solids, injectable gels, or emulsified micells(oil in water or water in oil). A desirable feature of these liquid,solid and gel formulations is that they maintain a single bolus orpellet shape at the site of their placement. That is, they do not breakup as a multitude of smaller droplets or particles that migrate awayfrom their intended point of placement and/or by virtue of a resultantincrease in surface area greatly alter the intended release rate oftheir drug content.

The present invention relates generally, but not totally, to the use ofcompounds that are syringible, of limited solubility, biocompatible andbiodegradable for controlled and sustained release of an agent or acombination of an agents. Solid, gel, or injectable controlled-sustainedrelease systems can be fabricated by combining an excipient from thelist above and a beneficial agent. Systems can combine more than one ofthese excipients as well as more than one beneficial agent. Solid formsfor implantation can be produced by tableting, injection molding or byextrusion. Gel can be produced by vortex or mechanical mixing.Injectable formulations can be made by pre-mixing in a syringe or mixingof the excipient and the beneficial agent at the time of administration.

Solid form generally contains 1-60% of one or more of the excipients,20-80% for a gel and 50-99% for a liquid. The content of the therapeuticagent/agents can range from 10% to 90% of the formulation. The amount ofthese excipient/therapeutic agent formulations placed in the tumor canrange from about 2 to 20 μl or μg per ml of tumor volume. The sustainedrelease of the therapeutic agent/agents into the tumor can be controlledto last from several days to several years. In a timely fashion thetotal formulation disappears from the site with little or no aftereffects.

Solid, liquid or gel excipient/agent formulations can be implantedsurgically or implanted by trocar or needle introduction directly intothe brain tumor such as inoperable gliomas [typically using a proceduresimilar to that described by Emerich et al., 17 (7) Pharm. Res. 776-78(2000). For localized beneficial agent delivery, the systems of thepresent invention may also be surgically implanted in or near the siteof the tumor or the cavity left from tumor resection. An especiallyattractive procedure is contemplated which involves the phacoemulsiontechniques commonly used in cataract surgery. In this contemplatedprocedure the phacoemulsion device adapted for intracranial operation isinserted into the tumor and a portion of the tumor tissue is emulsifiedfor facile removal by irrigation. At this time a sustained releaseformulation might be administered for immediate therapy (possibly asteroidal anti-inflammatory for example). Removal of portions of tumortissue allows temporary relief of pressure, and the removed tissue canbe assayed to identify cell types. Knowledge of the cell types permitsthe selection of the best long term therapeutic agent or agents for thesubsequent injectable sustained release formulations to eradicate thetumor mass.

More specifically, an embodiment of the present invention provides for abiocompatible, biodegradable, syringeable liquid, implantable solid, andinjectible gel sustained release formulations of therapeutic agents forbrain tumors that may be inserted directly into brain tumors. Theseformulations comprise novel biocompatible and biodegradable syringeableliquid, implantable cohesive solids and injectable gel formulationsconveniently placed inside brain tumors for the sustained release ofbeneficial agents are obtained by admixing one or more of theexcipients: benzyl benzoate, esters of benzoic acid with straight,branched, or cyclic chain aliphatic alcohols having one to twenty carbonatoms wherein one of the hydrogen atoms on the aliphatic chain isreplaced with a hydroxyl group (e.g., such alcohols as methanol,ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol,t-butanol, n-pentanol, i-pentanol, neo-pentanol, n-hexanol,cyclohexanol, n-heptanol, n-octonol, n-nonanol, n-decanol, and thelike), mono, di and tri esters of O-acetylcitric acid, orO-proionylcitric acid, or O-butyrylcitric acid with C₁ to C₁₀ straightand branched chain aliphatic alcohols, mono, di, and tri esters ofcitric acid with C₁ to C₁₀ straight and branched chain aliphaticalcohols, diethylene glycol dibenzoate, triethylene glycol dibenzoate,dibenzoate esters of poly(oxyethylene) diols up to about 400 mwt,propylene glycol dibenzoate, dipropylene glycol dibenzoate, tripropyleneglycol dibenzoate, dibenzoate esters of poly(oxypropylene) diols up toabout 3000 mwt, poly(oxypropylene) diols up to about 3000 mwt, dimethylsulfone, and the various isomers of tocopherol, tocopherol acetate,tocopherol succinate, and tocopherol nicotinate; and the various isomersof the tocotrienols and their acetates, succinates and nicotinates,polymeric polycarbonate oligomers; polymers and copolymers of glycolicand lactic acids, with a large number of established and new agents forthe treatment of brain tumors.

Such agents include tetrahydrocortisol;4,9(11)-pregnadien-17α,21-diol-3,20-dione (Anecortave acetate, Retaane,Alcon, Inc.); 4,9(11)-pregnadien-17α,21-diol-3,20-dione-21-acetate;11-epicortisol; 17α-hydroxyprogesterone; tetrahydrocortexolone;cortisone; cortisone acetate; hydrocortisone; hydrocortisone acetate;fludrocortisones; fludrocortisone acetate; fludrocortisone phosphate;prednisone; prednisolone; prednisolone sodium phosphate;methylprednisolone; methylprednisolone acetate; methylprednisolonesodium succinate; triamcinolone; triamcinolone-16,21-diacetate;triamcinolone acetonide; triamcinolone acetonide-21-acetate;triamcinolone acetonide-21-disodium phosphate; triamcinoloneacetonide-21-hemisuccinate; triamcinolone benetonide; triamcinolonehexacetonide; fluocinolone; fluocinolone acetate; fluocinoloneacetonide; dexamethasone; dexamethasone-21-acetate;dexamethasone-21-(3,3-dimethylbutyrate); dexamethasone-21-phosphatedisodium salt; dexamethasone-21-diethylaminoacetate;dexamethasone-21-isonicotinate; dexamethasone-21-dipropionate;dexamethasone-21-palmitate; betamethasone; betamethasone-21-acetate;betamethasone-21-adamantoate; betamethasone-17-benzoate;betamethasone-17,21-dipropionate; betamethasone-17-valerate;betamethasone-21-phosphate disodium salt; beclomethasone; beclomethasonedipropionate; diflorasone; diflorasone diacetate; mometasone furoate;acetazolamide (Diamox); naproxen; naproxin sodium salt; diclofenac;diclofenac sodium salt; celecoxib; rofecoxib; valdecoxib; etoricocib;lumiracoxib; sulindac; sulindac sodium salt; diflunisal; diflunisalsodium salt; piroxicam; indomethacin; indomethacin sodium salt;etodolac; etodolac sodium salt; meloxicam; ibuprofen; ibuprofen sodiumsalt; ketoprofen; ketoprofen sodium salt; r-flurbiprofen (MyriadGenetics, Inc.); mefenamic; mefenamic sodium salt; nabumetone; tolmetin;tolmetin sodium salt; ketorolac bromethamine; ketorolac tromethamine(Todardol®, Sytex, SA); ketorolac acid; choline magnesium trisalicylate;aspirin; salicylic acid; salicylic acid sodium salt; salicylate estersof alpha, beta, gamma-tocopherols (and all their d, 1, and racimicisomers); tenoxicam; aceclofenac; nimesulide; nepafenac; amfenac;bromfenac; flufenamate; phenylbutazone; CV 247 (Ivy Medical Chemicalsplc); pegaptanib octasodium; ranibizumab (Lucentis®, Genentech, Inc.);2-methoxyestradiol; shark cartilage extract (Neovastat, Aeterna);NX-278-L ant-VEGF aptamer (EyeTech); squalamine (MSI-1246, Genaera);2′-O-methoxyethyl) antisense C-raf oncogene inhibitor (ISIS-13650);vitronectin and osteopontin antagonists (3-D Pharm.); combretstatin A-4phosphate (CA4P, Oxigene); Fab fragment alpha-V/beta-1 integrinantagonist (Eos-200-F, Protein Design Labs); alpha-v/beta-3 integrinantagonist (Abbott); matrix metalloprotienase inhibitor (ISV-616, InSiteVision); matrix metalloprotienase inhibitor (TIMP-3, NIH); urokinaseplasminogen activator fragment (A6, Angstrom Pharm.); vascularendothelial growth factor antagonist (AAV-PEDF, Chiron); kdr tyrosinekinase inhibitor (EG-3306, Ark Therapeutics); cytochalasin E (NIH);kallikrinin-binding protein (Med. Univ. of So. Carolina); combretastatinanalog (MV-5-40, Tulane Univ.); pigment-epithelium derived growth factor(Med. Univ. So. Carolina); pigment-epithelium derived growth factor(AdPEDF, GenVec/Diacrin); plasminogen kringle (Med. Univ. So. Carolina);rapamycin; cytokine synthesis inhibitor/p38 mitogen-activated proteinkinaseinhibitor (SB-220025, GlaxoSmithKline); vascular endothelialgrowth factor antagonist (SP-(V5.2)C, Supratek Pharm. Inc.); vascularendothelial growth factor antagonist (SU10944, Sugen/Pfizer); vascularendothelial growth factor antagonist (VEGF-R, Johnson &Johnson/Celltech); vascular endothelial growth factor antagonist(VEGF-TRAP, Regeneron); FGF1 receptor antagonist/tyrosine kinaseinhibitor (Pfizer/Sugen); endostatin, vascular endothelial growth factorantagonist (EntreMed); bradykinin B1 receptor antagonist (B-9858,Cortech); bactericidal/permeability-increasing protein (BPI, Xoma);protein kinase C inhibitor (Hypericin, Kansai Med. Univ.);ruboxistaurinn mesylate (LY-333531, Eli Lilly); polysulphonic acidderivatives (Fuji Photo Film); growth factor antagonists (TBC-2653,TBC-3685, Texas Biotechnology); Tunica internal endothelial cell kinase(Amgen); acetylcysteine; mannitol; antineoplaston; humancorticotropin-releasing factor; VN40101M (Pediatric Brain TumorConsortium); everolimus; GW572016 (NCI); thalidomide; temozolomide;tariquidar; doxorubicin; dalteparin; tarceva; CC-5013 (NCI); hCRF(Xerecept, Neurobiological Technologies); bevacizumab (Avastin,Genentech); melphalan; thiotepa; depsipeptide; erlotinib; tamoxifen;bortezomib; lenalidomide; vorinostat; temsirolimus; modifinil;enzastuarin; motexafin gadolinium; F-18-OMFD-PET (Advanced BiochemicalCompounds, Redeberg); pemetrexed disodium; ZD6474 (NCI); valproic acid;vincristine; irinotecan; PEG-interferon alpha-2b; procarbazine;lonafarnib; arsenic trioxide; GP96 (Univ. Cal. S.F.); carboplatin;cyclophosphamide; 1311-TM-601 (Trans Molecular); lapatinib;O6-benzylguanine; TP-38 toxin (NCI); cilengitide; poly-ICLC (NCI);FR901228 (NCI); TransMid™ (Xenova); talabostat; ixabepilone; AEE788(Jonson Comprehensive Cancer Center); sirolimus; alanosine; sorafenib;efaproxiral; carmustine; iodine I 131 monoclonal antibody TNT-1/B (NCI);intratumoral TransMid™; topatecan; lomustine; phosphorus 32;18F-fluorodeoxyglucose (Alberta Cancer Board); vinblastine; BMS-247550(NCI); CC-8490 (NCI); IL 13-PE38QQR (Neopharm); imatib mesylate;hydroxyurea; G207 (MediGene); radiolabeled monoclonal antibody;2-deoxyglucose; talampanel; retinoic acid; gefitinib; tipifarnib; CPT-11(Kentuckiana Cancer Inst); rituximab; efaproxiral; PS-341 (FDA OfficeOrphan Product Development); capecitabine; G-CFS (NCI); vinorelbine;DCVax®-Brain (Northwest Biotherapeutics); paclitaxel; patipilone(Norvartis); iressa; methotrexate; ABT-751 (NCI); oxaliplatin; MS-275(NCI); trastuzumab; pertuzumab; PS-341 (NCI); 17AAG (NCI); lenalidomide;campath-1H; somatostatin analog; resveratrol; CEP-7055 (Cephalon);CEP-5214 (Cephalon); PTC-299 (PTC Therapeutics); inhibitors ofhepatocyte growth factor (L2G7 mAb, Galaxy Biotech); statins such asatorvastatin (Lipitor®, Pfizer), fluvastatin (Lescor®, Novartis),rosuvastatin (Crestor®, Astra Zeneca), prevastatin (Provacol®, TevaPharm.), simvastatin Zocar®, Merck & Co., Inc.), lovastatin (Mevorcor®,Merck) or cervastatin (Baycol®, Bayer AG) (HMG-CoA reductaseinhibitors); and Receptor tyrosine kinase inhibitors.

Such agents also include Anti-neovascularization steroids such as21-nor-5β-pregnan-3α,17α,20-triol-3-acetate;21-nor-5α-pregnan-3α,17α,20-triol-3-phosphate;21-nor-5β-pregn-17(20)en-3α,16-diol; 21-nor-5β-pregnan-3α,17β,20-triol;20-acetamide-21-nor-5β-pregnan-3α,17α-diol-3-acetate; 3βacetamido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate;21-nor-5α-pregnan-3α,17β,20-triol;21α-methyl-5β-pregnan-3α,11β,17α,21-tetrol-20-one-21-methyl ether;20-azido-21-nor-5β-pregnan-3α,17α-diol;20(carbethoxymethyl)thio-21-nor-5β-pregnan-3α,17α-diol;20-(4-fluorophenyl)thio-21-nor-5β-pregnan-3α,17α-diol;16α-(2-hydroxyethyl)-17β-methyl-5β-androstan-3α,17α diol;20-cyano-21-nor-5β-pregnan-3α,17α-diol;17α-methyl-5β-androstan-3α,17β-diol; 21-nor-5β-pregn-17(20)en-3α-ol;21-or-5β-pregn-17(20)en-3α-ol-3-acetate;21-nor-5-pregn-17(20)-en-3α-ol-16-acetic acid 3-acetate;3β-azido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate; and5β-pregnan-11β,17α,21-triol-20-one; 4-androsten-3-one-17β-carboxylicacid; 17α-ethynyl-5(10)-estren-17β-ol-3-one; and17α-ethynyl-1,3,5(10)-estratrien-3,17β-diol.

Another aspect of the present invention provides for embodimentscomprising omega-3 fatty acids. The health benefits of dietarysupplements of omega-3 fatty acids and their esters are well known. Theparticularly important omega-3 fatty acids in human nutrition areα-linolenic acid (ALA, C18H30O2, fw 278.4) eicosapentaenioc acid (EPA,C20H30O2, fw 306.5) and docosahexaenoic acid (DHA, C22H32O2, fw 328.5).The term omega-3 signifies that the first double bond exists between thethird and second carbon atoms counting from the terminal methyl at theopposite end of the chain from the carbonyl group.

The human body cannot synthesize EPA or DHA except by using ALA as anintermediate. But the presence of EPA and DHA in almost all tissues ofthe body indicates the importance of these compounds to the body andthus the judicious injection into the body of their therapeuticformulations will be safe, efficient and effective. These benefits alsoextend to the simple esters of EPA and DHA of the C₁ to C₈ straight andbranched chain aliphatic alcohols such as ethyl EPA and ethyl DHA.Recently, the FDA has approved ethyl EPA and ethyl DHA for dietarysupplements. One important property of these ethyl esters is that theycan be fractionally distilled from their readily available but crudesource, fish oil. This purification process provides the EPA and DHAesters free from possible heavy metal and PCB contaminants. Thus, thereremains a need for the development of these purified esters as liquidexcipient vehicles for injectable sustained drug release in variousareas of the human or animal body.

The embodiments thus provide for the novel concept of injections ofomega-3 fatty acids and their esters by themselves or as novel andtherapeutic formulations with active agents directly into strategicareas of the human or animal bodies to provide for the sustained releaseof the omega-3 compounds and therapeutic but nontoxic levels of theactive agents for periods of months to over a year.

Yet another embodiment of the present invention relates generally tonovel injectable and topically applied formulations containing bothsteroids and antioxidants. Specifically, the inclusion of antioxidantswith steroids addresses the problem that many steroids have harmful sideeffects arising from their being initiators of destructive oxidative andphoto-oxidative radical chain reactions. These novel steroid-antioxidantformulations are designed to be injected into the eye, joints, organs,or to be applied topically externally for the known steroid therapies ofanti-inflammation and regulation of metabolic and immune functions, butalso due to the presence of antioxidants to suppress damaging oxidativefree radical reactions initiated by the steroids in addition to harmfuloxidative chemistries normally present in cells.

Although oxygen is required for many life sustaining metabolic reactionsit also has damaging chemistries with cellular components. These harmfulchemistries involve the very reactive oxygen components: superoxideradicals, hydrogen peroxide, hydroxyl radicals, and organic peroxidesand hydroperoxides. Polyunsaturated lipids are important components ofcells, but they are major substrates for oxidative attack leading tocell death. Thus, the dependence of cells on oxygen places them aprecarious position between the prolife and toxic chemistries of oxygen.To tip the delicate balance towards life, nature provides cells withprotective antioxidant molecules such as tocopherol, ascorbic acid,glutathione, melatonin, carotenes, carnitine and others. The naturallevel of tocopherol in the human lens is around 2.2 μg/ml (Yeum et al.,19 (6) Curr. Eye Res. 502-05 (1999)), and the ascorbate level in tearsis 3.52 μg/ml (Choy et al., 80 (9) Optom. Vis. Sci. 632-36 (2003)).Unfortunately the exposure of cells to some steroids, even though forvery necessary therapeutic reasons, has been found to tip this balancetowards the toxic side. For it has been demonstrated that thesesteroids, especially the glucocorticosteroids such as triamcinolone anddexamethasone, readily interact with oxygen and/or light to becomeinitiators of damaging oxidative chain reactions. Miolo et al., 78 (5)Photochemistry & Photobiology, 425-30 (2003); Calza et al., 12 (12) J.Am. Soc. Mass. Spectrom., 1286-95 (2001). Although the co-administrationof certain antioxidants with certain steroids has been shown toameliorate the toxic oxidative processes initiated by the steroids(Kosano et al., 76 (6) Exp. Eye Res., 643-48 (2001) and referencestherein), presently most commercial injectable steroid formulations donot include antioxidants. See Fact sheet inserts for Kenalog™,Bristol-Myers Squibb, 2006; Depo Medrol™, Pharmacia, 2003; Decadron™,Merck Sharp & Dohme, 1995, (contains bisulfites, hydroxybenzoate esterswhich might have antioxidant effects). In formulating compositionscontaining antioxidant supplements one must be very careful not to addtoo high a level of antioxidants, however, because it has beendemonstrated that at high levels many of these antioxidants actually arepro-oxidants and may increase oxidative damage. Bowry et al., 270 J.Biol. Chem. 5756-63 (1995); Halliwell, 25 Free Rad. Res. 439-54 (1996).Using the naturally occurring antioxidants and mimicking their levels inthe cell environment would be good practice.

The areas of therapy of particular interest for applying theformulations of this invention involve intraocular injections (for theindications: cystoid macular edema, exudative age-related maculardegeneration, proliferative diabetic retinopathy, diabetic macularedema, choroidal neovascularization, retinal vein occlusion, uveitis);intra-articular injections (for the indications: synovitis ofosteoarthritis, rheumatoid arthritis, bursitis, gouty arthritis,epicondylitis, nonspecific tenosynovitis, post-traumaticosteoarthritis); and topical applications on the body exterior. Thesteroid components and excipients of these novel formulations and theirtherapeutic effects are well described herein and in U.S. PatentApplication Publication No. 2006/0073182. The possible adverse effectsof the steroids used in these formulations are in many cases believed toarise from the aforementioned damaging oxidative chemistries initiatedby these steroids in the absence of proper antioxidants. The environmentof the eye is particularly damaging for it is exposed to both oxygen andlight energy. The phenolic or quinone-like structures of the steroidmolecules readily absorb UV-A and UV-B radiation to convert thesemolecules to unpaired electron radical species. These radical speciescan damage cell components (especially unsaturated lipids in cellmembranes) or they can interact with oxygen to instigate damaging peroxychain reactions leading to cataracts (Nishigori et al., 35 (9) Life Sci.981-85 (1984); Boscia et al., 41 (9) Invest. Opthalmol. Vis. Sci.2461-65 (2000)), and glaucoma (Sacca et al., 84 (3) Exp. Eye Res. 389-99(2007)). Cataract formation and glaucoma are maladies associated withsteroid therapies in the eye. In the case of intra-articular steroidtherapies repeated injections are avoided because they lead to cartilageand bone degeneration. Reactive oxygen species have been identified ascausative agents. Kim et al., 49 (9) Free Radic. Biol. Med. 1483-93(2006).

Without further elaboration, one skilled in the art having the benefitof the preceding description can utilize the present invention to thefullest extent. The following examples are illustrative only and do notlimit the remainder of the disclosure in any way.

EXAMPLES Example 1 Preparation of a Poly(1,3-propanediol carbonate) Ifrom 1,3-propanediol at 65° C. and 96 hours

To 23.6 g (0.2 mole) diethyl carbonate (b.p. 128° C.) was added 15.2 g(0.2 mole) 1,3-propanediol containing 0.05 g (1.25 mmole) of metallic Nato give two liquid phases. These reactants were placed in an opencontainer in a 65° C. oven and were shaken occasionally. After 12 hours,the reactants were a homogeneous solution weighing 38.0 g. Thetheoretical weight for the loss of 0.4 moles (18.4 g) of ethanol in acomplete reaction would be 20.4 g. The heating and occasional shakingwere continued to give 27.0 g at 24 hours, 23.2 g at 48 hours, 21.4 g at72 hours, and 17.4 g at 96 hours. The product oil was washed with 15 ml5% aqueous acetic acid to two phases. The top phase was the watersoluble phase. The 10.5 ml bottom phase was washed with 15 ml water togive 7.5 ml of a poly(1,3-propylene glycol carbonate) oligomer as awater-insoluble oil.

Example 2 Preparation of Poly(1,3-propanediol carbonate) II from1,3-propanediol at 110-150° C. and 26 hours.

A mixture of 76 g (1.0 mole) 1,3-propanediol containing 0.1 g metallicNa (2.5 mmole) and 118 g (1.0 mole) diethyl carbonate was heated at 110°C. As soon as the reactants reached 60° C. they formed a homogeneoussolution. After heating 8 hours, the reactants had lost 48 g (52% oftheoretical amount of ethanol). The temperature was then raised to 150°C. After 10 hours, the reactants lost another 46 g. A drop of thisproduct completely dissolved in water. The resultant 97 g of oil wasmixed with 6 g (0.05 moles) diethyl carbonate and the resultant solutionwas heated with occasional stirring at 150° C.

After 8 hours, the resultant syrup was found to be partially insolublein water. The product was washed with 100 ml 5% aqueous acetic acidfollowed by four washings with 100 ml portions of water to give 46.1 gslightly yellow viscous oil (46.1/102=45% yield).

Example 3 Preparation of a Poly(di-1,2-propylene glycol carbonate) fromdi-1,2-propylene glycol

To 590 g (0.5 moles) diethyl carbonate was added 67.0 g (0.5 moles)di-1,2-propylene glycol which had been reacted with 0.02 g Na to form ahomogeneous solution. The reactants were placed in an open flask at 100°C. After 12 hours, the solution lost 23.4 g (about 50% of thetheoretical 46 g ethanol). After another 15 hours at 150° C. thereactants had lost a total of 53.2 g to give a syrup that was partiallyinsoluble in water. The product was washed with 100 ml 5% aqueous aceticacid followed by four washing with 100 ml portions of water to give 25.2g colorless viscous, water insoluble liquid poly(di-1,2-propylene glycolcarbonate) oligomer.

Example 4 Preparation of a Poly(tri-1,2-propylene glycol carbonate) fromtri-1,2-propylene glycol

To 0.1 g Na metal was added t 96.0 g (0.5 mole) tri-1,2-propyleneglycol. After 5 minutes, the Na had reacted leaving a light yellow oil.59.0 g (0.5 mole) diethyl carbonate was added to this liquid and theresultant homogeneous solution was heated to 110° C. in an open flask.After 6 hours, the reactants lost 28.0 g (61% of theory). The yellowsolution was then heated at 125° C. for 8 hours, whereupon the reactantshad lost a total of 48 g (104% of theory). Another 6.0 g (0.5 moles)diethyl carbonate were added and the temperature was raised to 150° C.After 6 hours, the viscous yellow-brown product solution was washed with100 ml 5% aqueous acetic acid followed by 4 washings with 100 mlportions of water to give 48 g of a viscous orange, water insolubleliquid oligomer.

Example 5 The Assay Procedure for Measuring the Release Profiles ofDexamethasone or Triamcinolone Acetonide from their Sustained ReleaseFormulations (SRF)

The vials for the release studies were labeled and the weight of eachvial was recorded. To each vial was added 3-4 grams of 0.9% salinesolution and the weight was recorded. Then the SRF was injected orplaced at the bottom of the vial. The weight of the SRF was recorded. Anadditional amount of 0.9% saline solution was added to a total of 10grams of saline. The resulting vial was kept in an incubator or waterbath at 37° C. Samples were taken periodically to measure the releaseprofile of dexamethasone or triamcinolone acetonide using a HPLCinstrument. Sampling protocol was carried out according to the followingprocedure: Using a disposable pipette, 8 grams of the saline solutioncontaining dexamethasone or triamcinolone acetonide was withdrawncarefully from each vial. 8 grams of 0.9% saline solution was then addedto each vial. The vials were kept at 37° C. after sampling.

The HPLC analysis was carried out using a Beckman Gold Instrument withan autosampler. Calibrators with three different concentrations ofdexamethasone or triamcinolone acetonide in water were prepared.Calibrators and samples were injected onto a C18 column (Rainin, 250×4.6mm) containing a guard column (C18, 4.6 mm×1 cm) and analyzed,respectively. The column was eluted using a mobile phase of 45% (or 50%)acetonitrile/water, flow rate 1.0 mL/min, and 7 (or 6) minute run timeat an ambient temperature. The detector wavelength of 238 nm was used.The dexamethasone or triamcinolone acetonide (retention times, 6-4minutes) concentration of each sample was calculated from the standardcurve using the software of the Beckman Gold instrument.

A wash program to clean the HPLC column was set up during the HPLC run.After every three or four injections, a sample containing 20 μL ofacetonitrile was injected onto the column, the column was eluted with amobile phase of 99% acetonitrile/water, flow rate 1 mL/min, and a runtime 7 minutes. Then the column was equilibrated back to the originalmobile phase by injecting 20 μL of acetonitrile, eluting with 45% (or50%) acetonitrile/water, flow rate 1 mL/min, and a run time 7 minutes.

The sampling times and the active ingredient (for example dexamethasoneor triamcinolone acetonide) concentrations determined from HPLC wererecorded and tabulated. The percent drug released and the amount of drugreleased were each calculated from a Microsoft Excel software program.

Example 6 Preparation of mixtures of dexamethasone inpoly(1,3-propanediol carbonate) I and their release profiles

Preparation of 10% dexamethasone in poly(1,3-propanediol carbonate) I:One portion by weight of dexamethasone was mixed with nine portions byweight of the poly(1,3-propanediol carbonate) I prepared in Example 1.The resulting suspension was stirred at an ambient temperature until ahomogeneous mixture formed. The mixture was then aliquoted and analyzedfor the release profile as shown in FIG. 1.

Preparation of 20% dexamethasone in poly(1,3-propanediol carbonate) I:Two portions by weight of dexamethasone were mixed with eight portionsby weight of the poly(1,3-propanediol carbonate) I prepared inExample 1. The resulting suspension was stirred at an ambienttemperature until a homogeneous mixture formed. The mixture was thenaliquoted and analyzed for the release profile as shown in FIG. 1.

Example 7 Preparation of mixtures of dexamethasone inpoly(1,3-propanediol carbonate) II and their release profiles

Preparation of 5% dexamethasone in poly(1,3-propanediol carbonate) II:One portion by weight of dexamethasone was mixed with nineteen portionsby weight of the poly(1,3-propanediol carbonate) II prepared in Example2. The resulting suspension was stirred at an ambient temperature untila homogeneous mixture formed. The mixture was then aliquoted andanalyzed for the release profile as shown in FIG. 2.

Preparation of 10% dexamethasone in poly(1,3-propanediol carbonate) II:One portion by weight of dexamethasone was mixed with nine portions byweight of the poly (1,3-propanediol carbonate) II prepared in Example 2.The resulting suspension was stirred at an ambient temperature until ahomogeneous mixture formed. The mixture was then aliquoted and analyzedfor the release profile as shown in FIG. 2.

Example 8 Preparation of mixtures of dexamethasone inpoly(di-1,2-propylene glycol carbonate) and their release profiles

Preparation of 5% dexamethasone in poly(di-1,2-propylene glycolcarbonate): One portion by weight of dexamethasone was mixed withnineteen portions by weight of the poly(di-1,2-propylene glycolcarbonate) prepared in Example 3. The resulting suspension was stirredat an ambient temperature until a homogeneous mixture formed. Themixture was then aliquoted and analyzed for the release profile as shownin FIG. 3.

Preparation of 10% dexamethasone in poly(di-1,2-propylene carbonate):One portion by weight of dexamethasone was mixed with nine portions byweight of the poly(di-1,2-propylene glycol carbonate) prepared inExample 3. The resulting suspension was stirred at an ambienttemperature until a homogeneous mixture formed. The mixture was thenaliquoted and analyzed for the release profile as shown in FIG. 3.

Preparation of 20% dexamethasone in poly(di-1,2-propylene glycolcarbonate): Two portions by weight of dexamethasone were mixed witheight portions by weight of the poly(di-1,2-propylene glycol carbonate)prepared in Example 3. The resulting suspension was stirred at anambient temperature until a homogeneous mixture formed. The mixture wasthen aliquoted and analyzed for the release profile as shown in FIG. 3.

Example 9 Preparation of mixtures of dexamethasone inpoly(tri-1,2-propylene glycol carbonate) and their release profiles

Preparation of 5% dexamethasone in poly(tri-1,2-propylene glycolcarbonate): One portion by weight of dexamethasone was mixed withnineteen portions by weight of the poly(tri-1,2-propyleneglycolcarbonate) prepared in Example 4. The resulting suspension was stirredat an ambient temperature until a homogeneous mixture formed. Themixture was then aliquoted and analyzed for the release profile as shownin FIG. 4.

Preparation of 10% dexamethasone in poly(tri-1,2-propylene glycolcarbonate): One portion by weight of dexamethasone was mixed with nineportions by weight of the poly(tri-1,2-propylene glycol) carbonateprepared in Example 4. The resulting suspension was stirred at anambient temperature until the formation of a homogeneous mixture. Themixture was then aliquoted and analyzed for release profile as shown inFIG. 4.

Example 10 Preparation of Mixtures of Dexamethasone in Benzyl Benzoateand their Release Profiles

In preparing 20% dexamethasone in benzyl benzoate, two portions byweight of dexamthasone was mixed with eight portions by weight of benzylbenzoate. The resulting suspension was stirred at an ambient temperatureuntil a homogeneous mixture formed. The mixture was then aliquoted andanalyzed for the release profile as shown in FIG. 5.

Formulations containing 5% and 50% dexamethasone in benzyl benzoate wereprepared under similar conditions to the 20% formulation, with theexception of the weight ratio of dexamethasone/benzyl benzoate. Mixturesof 5% and 50% dexamethasone in benzyl benzoate were prepared, and theresulting mixtures were aliquoted and small portions were analyzed forthe release profiles as shown in FIG. 5.

Dexamethasone in benzyl benzoate forms a uniform suspension. Aformulation of 25% is easily syringeable. As the suspension is slowlyinjected into the eye's posterior segment, a uniform spherical deposit(reservoir) is formed in the vitreous body. Dexamethasone is thenreleased slowly into the vitreous humor of the posterior segment.Dexamethasone and benzyl benzoate are eventually metabolized tobyproducts to be excreted in the urine.

Example 11 Preparation of Mixtures of Dexamethasone in Diethylene GlycolDibenzoate and their Release Profiles

Ten percent dexamethasone in diethylene glycol dibenzoate was preparedby mixing one portion by weight of dexamethasone (Dex) with nineportions by weight of diethylene glycol dibenzoate. The resultingsuspension was stirred at an ambient temperature until a homogeneousmixture formed. The mixture was then aliquoted and analyzed for therelease profile as shown in FIG. 6.

Using conditions similar to that of the 10% Dex/diethylene glycoldibenzoate preparation, with the exception of the weight ratios,mixtures of 5% and 25% Dex/diethylene glycol dibenzoate formulationswere prepared. The resulting mixtures were aliquoted and small portionsanalyzed for the release profiles as described previously. The resultingrelease profiles are shown in FIG. 6.

Example 12 Preparation of Mixtures of Triamcinolone Acetonide inDiethylene Glycol Dibenzoate and their Release Profiles

Preparations of 5%, 10% and 25% triamcinolone acetonide in diethyleneglycol dibenzoate were prepared as follows: a 0.5, 1.0, or 2.5 portionby weight of triamcinolone acetonide was mixed with a 9.5, 9.0 or 7.5portion by weight, respectively, of diethylene glycol dibenzoate. Theresulting suspension was stirred at an ambient temperature until ahomogeneous mixture formed. The mixture was then aliquoted and analyzedfor the release profile as described previously. The resulting releaseprofiles are shown in FIG. 7.

Example 13 Preparation of mixtures of dexamethasone in d-tocopherol ord,1-tocopherol acetate and their release profiles

For the preparation of 10% Dex in d-tocopherol, one portion by weight ofDex was mixed with nine portions by weight of d-tocopherol. Theresulting suspension was stirred at an ambient temperature until ahomologous mixture formed. The mixture was then aliquoted and analyzedfor release profile as shown in FIG. 8.

For the preparation of 20% Dex in d-tocopherol, two portions by weightof Dex was mixed with eight portions by weight of d-tocopherol. Theresulting suspension was stirred at an ambient temperature until theformation of a homologous mixture. The mixture was then aliquoted andanalyzed for release profile as shown in FIG. 8.

For the preparation of 50% Dex in d1-tocopherol acetate, five portionsby weight of Dex were mixed with five portions by weight ofd1-tocopherol acetate. The resulting suspension was stirred at ambienttemperature until a homologous mixture formed. The mixture was thenaliquoted and analyzed for the release profile as shown in FIG. 8.

Example 14 Manufacturing of a Solid Drug Delivery System withDexamethasone and Diethylene Glycol Dibenzoate and its Release Profile

Dexamethasone powder and diethylene glycol dibenzoate by weight weremixed thoroughly by mortar and pestle. The mixture was placed into aParr pellet press of 2 mm diameter to form a solid pellet at 25° C.suitable for an implant. The newly formed pellet was then weighed in amicrobalance before testing for in vitro kinetics as shown in FIG. 9.

Example 15 Manufacturing of a Solid Drug Delivery System withDexamethasone and Benzyl Benzoate and its Release Profile

Dexamethasone powder and benzyl benzoate by weight were mixed thoroughlyby mortar and pestle. The mixture was then placed into a 2 mm diameterParr pellet press to form a pellet at 25° C. suitable for an implant.The formed pellet was weighed and recorded in a microbalance beforetesting for in vitro kinetics as shown in FIG. 10.

Example 16 Manufacturing of a Solid Drug Delivery System withDexamethasone and Tocopheryl Succinate and its Release Profile

Dexamethasone powder and tocopheryl succinate powder were thoroughlymixed at a ratio of 50/50 by weight. The well-mixed powder was filledinto a single barrel extruder and heated for 1 hour at 65° C. beforeextruding through a 1 mm orifice. Micropellets of varying sizes suitablefor implants were cut from the extruded filaments for in vitro kinetictesting as shown in FIG. 11.

Example 17 Combination Formulations

Combination with two or more drugs conveniently formulated with anexcipient such as benzyl benzoate provides for sustained and controlledrelease of the active agents. The variables of volume, concentration andpercentages of the ingredients are factors influencing duration andtherapeutic concentration of the drug(s) released. As an example, in a20% (wt) formulation of a 1:1 dexamethasone:ciprofloxacin in benzylbenzoate, the release profile of the two drug is similar and theduration is about twenty-eight to thirty-five days. The release profileof the two drugs is shown in FIG. 12 A.

Another useful composition comprises dexamethasone and ciproloxin at aratio of 3:1 dexamethasone:ciprofloxacin. The duration of release ofeach drug is prolonged significantly, to about sixty days fordexamethasone and longer for ciprofloxacin, as shown in FIG. 12 B.

Example 18 Pharmacokinetics and Metabolism of Injected FormulationComprising Dex

To examine the in vivo release of dexamethasone in vivo, a compositionof 25% dexamethasone by weight in benzyl benzoate (DB) was used: 25 μl(low dose) contained 6 mg dexamethasone, 50 μl (high dose) contained 12mg dexamethasone. Benzyl benzoate (BB) served as placebo.

The in vivo release of the DB composition was studied in twenty-fourrabbits. Twenty-five μl of 25% DB was injected into the posteriorsegment of one eye of twelve animals and the contralateral eye receiveda placebo. Another twelve animals received 50 μl of the DB in one eyeand 50 μl of the BB placebo in the second eye. Animals were euthanizedat the appropriate time points and vitreous humor samples were removedsurgically. Dexamethasone concentration was determined by high pressureliquid chromatography (HPLC) as described in Example 5.

For the high dose, the concentration of released dexamethasone wasmaximal during the first week after insertion, with a mean of 5.56 μg/mlfrom Day 7 to Day 90, declining to a mean level of 1.85 μg/ml by Day 90.With the low dose, the mean level of dexamethasone was 2.8 μg/ml fromDay 7 to Day 60, declining to a mean level of 0.8 μg/ml. See FIG. 13.Dexamethasone was not detected in any of the control eyes.

Clinically, the 24 animals receiving the placebo or low or high doses ofthe DB showed no evidence of inflammation or infection for the entirestudy. Animals were examined twice weekly both by slit-lampopthalmoscopy and fundoscopic examination. No evidence of cataracts,vitreous, or retinal abnormality was observed.

Regarding histopathology, three animals were injected with 25 μl of theDB in one eye and 25 μl of the placebo (BB) in the contralateral eye.Another three animals were injected with 50 μl DB in one eye and 50 μlBB in the other eye. They were followed clinically weekly and weresacrificed for histopathology at 30 days for the low dose and at 90 daysfor the high dose. Eyes were fixed in 10% buffered formalin and examinedafter H & E staining. The anterior segment comprising the cornea,anterior chamber, iris, ciliary body, and lens were normal. The pigmentepithelium, Bruch's membrane, and the choroids were all within normallimits. See FIG. 14. There were no obvious differences in thehistopathology between the treated and control eyes.

To further examine the in vivo anti-inflammatory effect of DB, 25 μl of25% DB was injected into the vitreous of one eye of three New ZealandWhite (NZW) rabbits weighing 3 kg-3.5 kg. Twenty-four hours later, 2.5mg of bovine serum albumin (BSA) was injected into both eyes. Theanimals were examined daily as well as opthalmologically. Between 10 to14 days, uveitis with severe fibrinous reaction occurred in the eyeunprotected by DB. In the eyes injected with DB, little to noinflammation was detected on examination. Histopathology, theunprotected eye showed chronic and acute inflammatory cells in the uvealtissues as well as in the anterior chamber and the vitreous cavity. Inthe protected eye, there was minimal evidence of inflammation with fewround cell infiltration in the choroids. The cornea, iris, retina andthe choroids were histologically intact. See Table 1 below. TABLE 1Inflammation in NZW NZW Day 0 Day 14 1 OD BSA/DB* 3+ OS BSA 0-1+ 2 ODBSA 3-4+ OS BSA/DB Trace 3 OD BSA/DB 0   OS BSA 4+BSA: bovine serum albumin;DB: 25% dexamethasone/benzylbenzoateOD: right eye,OS: left eye;0-4: severity of posterior segment inflammation, 4+ being maximum

Another three NZW rabbits were immunized intravenously (IV) with 10 mgof BSA. Twenty-one days later, following intradermal injection of 0.5 mgBSA/0.1 ml saline, all animals demonstrated a strong (+4) Arthusreaction indicating the animals were systemically immuned to the BSA. Onday thirty, one eye of each animal was injected intravitreally with 25μl of a 25% DB composition, and 24 hours later 0.5 mg BSA/0.1 ml normalsaline was injected into both eyes. Severe uveitis developed andpersisted in the ensuing seven to ten days in the unprotected eye, whilethe protected eye was judged to be normal. On day sixty, repeat skintesting showed that the (+4) Arthus reaction remained intact, andreinjection of 0.5 mg BSA/0.1 ml normal saline showed similar protectionas observed on day 30. These studies imply that DB has immediate andsustained protective effect in the experimental eye. When these animalswere again challenged with 0.5 mg BSA/0.1 ml normal saline at 90 days,uveitis developed in all eyes, but the inflammation in the protected(DB) eye appeared to be less severe. See Table 2 below. Protectionagainst inflammation with 25 μl of DB lasted for sixty days. At ninetydays, there may have been an insufficient therapeutic level ofDexamethasone in the eye. TABLE 2 Inflammation in protected andunprotected NZW eyes. NZW Day 0 Day 14 Day 30 Day 60 Day 90 1 OD BSA3-4+ 3-4+ 3-4+ OS BSA/DB* 0   0 2-3+ 2 OD BSA 4+ 3-4+ 3+ OS BSA/DB Trace  0+ 2-3+ 3 OD BSA 4+   4+ 4+ OS BSA/DB 0-1+ 0 2-4+BSA: bovine serum albumin;DB: 25% dexamethasone/benzylbenzoateOD: right eye,OS: left eye;0-4: severity of posterior segment inflammation, 4+ being maximum

Another three NZW rabbits were immunized similarly IV with 10 mg BSA.Twenty-four hours later, one eye of each animal was injected with 50 μlof 25% DB. At three months (90 days), intradermal skin testing evoked a+4 reaction. One week later, 0.5 mg BSA/0.1 ml normal saline wasinjected in both eyes of each animal. The protected eye (injected with50 μl 25% DB) showed little to no clinical uveitis when compared to thecontralateral unprotected eye. This indicates that chronic sustainedrelease of Dexamethasone was able to protect the eye up to three monthswhen challenged locally with BSA. See Table 3 below. TABLE 3 Sustainedprotection in protected NZW eyes. NZW Day 0 Day 90 1 OD BSA/DB* 0-1+ OSBSA 4+ 2 OD BSA/DB 0+ OS BSA 3-4+ 3 OD BSA/DB 0-1+ OS BSA 4+BSA: bovine serum albumin;DB: 25% dexamethasone/benzylbenzoateOD: right eye,OS: left eye;0-4: severity of posterior segment inflammation, 4+ being maximum

Example 19 Pharmacokinetics and Metabolism of Injected FormulationComprising TA

A composition of 25% TA (Triamcinolone Acetonide) by weight in benzylbenzoate (TA/B) was used: 25 μl containing 7.0 mg TA and 50 μlcontaining 14 mg TA. Benzyl benzoate (BB) served as placebo.

The in vivo release of the TA was studied in twenty-seven rabbits.Twenty-five μl (25 μl) of the composition was injected into theposterior segment of one eye of twelve animals and the contralateral eyereceived 25 μl of BB. Another twelve animals received 50 μl of the samecomposition into posterior segment of one eye and 50 μl BB into thesecond eye. Animals were euthanized at the appropriate time points (eachtime point n=3) and vitreous humor samples were removed surgically forTA concentration by high-pressure liquid chromatography (HPLC) asdescribed in Example 5. The mean vitreous concentration TA for the 50 μlTA/B at twenty-four hours was 3.25 μg/ml; at 1 month 2.45 μg/ml; atthree months 1.45 μg/ml; and at six months 1.56 μg/ml. The mean vitreousTA level over the 6 month period was 2.17 μg/ml. The mean vitreousconcentration of TA of the 25 μl TA/B animals was 1.78 μg/ml attwenty-four hours; 1.31 μg/ml at one week; 0.81 μg/ml at one month; 0.4μg/ml at three months; and 0.36 μg/ml at six months, with a mean of 0.93μg/ml over a six month period. TA was not detected in any of the controleyes. See FIG. 15. For the 25 μl dose, near zero-order release was beenobserved in vivo for 270 days (data not shown). For the 50 μl dose, nearzero-order release has been observed in vivo for 365 days (data notshown).

Clinically, the twenty-seven animals receiving the BB placebo showed noevidence of inflammation or infection for the entire study. Animals wereexamined twice weekly both by slit-lamp opthalmoscopy and fundoscopicexamination. No evidence of cataracts, vitreous or retinal abnormalitywas seen.

Regarding histopathology, six animals were injected with 50 μl of 25%TA/B in the right eye and 50 μl of BB in the other eye. They werefollowed clinically weekly and were sacrificed for histopathology at 180days. Eyes were fixed in 10% buffered formalin and examined after H & Estaining. The anterior segment comprising the cornea, anterior chamber,iris, ciliary body and lens was normal. Histopathology of the posteriorsegment (including the vitreous, retina, photoreceptors cells, pigmentepithelium, Bruch's membrane and the choroids) was within normal limits.There were no obvious differences in the histopathology between thetreated and the control eyes.

Example 20 Solid Implant Comprising Dex

The levels of dexamethasone released from a solid implant was studied inthe anterior chamber of a NZW rabbit. A mixture of 50:50 dexamethasone(Upjohn) and d1-alpha tocopherol succinate (Sigma) was extruded throughan aperture of 790 μM mm at 25° C. One (1) mgm of this extruded mixturewas surgically placed in the right anterior chamber of a 4 kg NZW femalerabbit. Sampling of the aqueous humor from the anterior chamber (AC) forHPLC dexamethasone analysis was performed in accordance with the aboveexample. Therapeutic sustained release levels of dexamethasone wereobserved. See FIG. 16. Clinically, the animal's eye was completelyquiescent and the composition was judged to be biocompatible.

Example 21 Sustained Release of Dexamethasone/d1-Alpha TocopherolSuccinate Coating of Stainless Steel Surface and Cardiac Stents

A mixture of 2:8:1 (wt) of dexamethasone:acetone:tocopherol succinatecoating was applied to two stainless steel tubing surfaces and twocommercial cardiac stents. Coating was achieved by dipping and ovendrying. Elution of dexamethasone for HPLC analysis was done in a 20 mldistilled water vial and exchange of 75% of the total volume took placeper period of assay. See FIG. 17. Tocopherol succinate has beendemonstrated to be an effective coating medium on steel surfaces forcontrolled drug release. The application of this methodology could beextended to various materials and surfaces including wood, glass,various metals, rubber, synthetic surfaces such as teflon, plastics,polyethylene tubings and the like.

Example 22 Formulations Comprising Cyclosporine in Tocopherol Succinate

To study the in vitro release of 25:75 d1-alpha tocopherol:CyclosporinA, cyclosporin was mixed with tocopherol succinate and extruded at 25°C. through an aperture of 790 μM. One mg (1 mg) of the material wasplaced in 10 ml distilled water vial and aliquots were sampled fordissolution as described above. See FIG. 18. Prolonged sustained releasein a linear fashion was observed for about 272 days.

To study the in vivo release profile, 0.75 mg of the 25:75 tocopherolsuccinate:cyclosporin was implanted surgically in the right anteriorchamber (AC) of the 4.0 kg NZW female rabbit. The AC was tapped at theabove time-points for HPLC determination of CsA in the aqueous humor.See FIG. 19. Additionally, 5.0 mg of 25:75 tocopherolsuccinate:cyclosporine was implanted surgically into the left posteriorsegment (PS) of a 4 kg NZW female rabbit eye. The vitreous humor in thePS was tapped at the above time-point for CsA HPLC analysis. See FIG.20.

In another in vivo release study, 30 mg (3×10 mg) of a 25:75 tocopherolsuccinate:cyclosporin formulation was extruded through a 1 mm aperture.The segments were implanted in the peritoneal cavity of an adult maleSprague-Dawley rat with a trocar through a 3 mm incision after local0.5% lidocaine infiltration. Cardiac puncture was performed for bloodCsA LCMSMS analysis. See FIG. 21.

Implants of cyclosporin:tocopherol succinate were injected by needletrocar in various organs in Sprague-Dawley rats to determine cyclosporindistribution. More specifically, extruded 20:80 tocopherolsuccinate:cyclosporin of various weights were implanted. After sacrificeand harvest, all tissues were dried in a tissue concentrator for 48hours, crushed and soaked in 1 ml of MeOH containing 10 ng/ml CsD.Analysis were performed with Mass Spec Liquid Chromatography. CsA wasobserved as indicated below in Table 4 and Table 5. Abbreviations: antanterior, post posterior, hem hemisphere. TABLE 4 Cyclosporindistribution in rat liver and brain. Upper lobe mg dried tissue ng/mlCsA ng/mg CsA Liver #1 Upper Lobe, Sacrificed Day 5, 2 mg 80% CsA intocopherol succinate was implanted into the right third of the middlelobe* right third 71.4. mg 2540 35.6 middle third 119.4 191 1.6 leftthird 88.4 184 2.1 middle lobe right third* 83.3 2360 28.3 left third 88878 10 left third 49.2 2620 53.2 blood na 0 na Observation: CsAdistribution was detected in both upper and middle lobes when implantwas implanted in the middle lobe.* Liver #2 Lower Lobe, Sacrifice 24hours, 2 mg of implant injected. right fifth 99.3 254 2.6 right middle59.6 144 2.4 fifth Implant* 138.8 2420 left middle 77.5 1710 22 fifthleft fifth 53.5 278 5.2 Observation: Sacrifice at 24 hours showed muchhigher concentration in the section of the liver containing the implant.Brain #1, Sacrifice 24 hours, 1 mg of the formulation was implanted.left ant hem 47.2 72.1 15.3 left post hem 79.3 180 2.3 right ant hem*52.7 1190 22.6 right post hem 60.8 385 6.3 blood na 0 na Observation:CsA distribution was noted in both hemispheres even though the implantwas placed in the right ant hem.* Brain #2, 1 mg formulation implantedin right ant hem.* left ant hem 42.2 478 11.3 left post hem 68.6 127 1.9right ant hem* 73.9 401 5.4 right post hem 113.7 96 0.8 blood na 0.29 naObservation: Similar to brain # 1, the left ant hem showed much higherconcentration.*Site of implantation.

TABLE 5 Cyclosporin distribution in rat spleen and kidney. mg driedtissue ng/ml CsA ng/mg CsA Spleen, sections right to left, 1 mg implantin section #7.* section #1 10.3 217 21.1 section # 2 16.2 72.5 4.5section #3 12.9 17.7 1.4 section #4 24.9 62 2.5 section #5 22.5 72.9 3.2section #6 26.8 101 3.8 section #7* 29 1800 62 Observation: Distributionappears higher at the opposite pole of the spleen. Kidney, 075 mgimplant in lower third. blood na 0 na upper third 156.8 314 2 middle85.5 333 3.9 lower third* 106.1 165 1.6 Observation: CsA distributionthroughout kidney.*site of implantation.

Example 23 Transdermal Delivery of Insulin

The comparison of injected versus transdermal delivery of severalformulation of insulin was studied in a mouse model. One mg of porcineinsulin was injected IP (intraperitoneal) into a mouse. A precipitousdrop in glucose level was found within one-half hour and developed intohypoglycemia after one hour. Hypoglycemia persisted below perceptiblelevels and the animals never recovered. One mg of porcine insulin wasmixed with 0.1 ml of tocopherol acetate and injected IP, perceptibledrop in glucose level was seen up to 3 hours and the animal remainedhypoglycemic and did not recover. IP glucose infusion did not reversethe hypoglycemia. One mg of porcine insulin mixed with 0.1 ml oftocopherol acetate was applied topically on the skin of a shaved mouse.A slow decline of the glucose level was seen, with the lowest leveldetermined at 5.5 hours. A return towards pre-treatment levels was seenat 24 hour and 48 hour. Tocopherol IP was able to slow the hypoglycemiceffect of insulin. Transdermal insulin w Topcopherol Ac producedreduction in glucose levels with slow recovery to pre-treatment levelsafter 24-48 hours. Sustained release of transdermally administeredinsulin was observed.

Porcine insulin (20 mg) was mixed in 199 mg/ml of tocopheryl acetate andformed a paste (or gel) which and was applied to the backs of shavedalbino mice as follows: Mouse #1 was treated with 39.8 mg ofinsulin/tocopherol acetate paste, equaling 3.6 mg of insulin; mouse #2was treated with 75.2 mg of insulin/tocopherol acetate paste, equaling6.9 mg of insulin. Tail blood glucose levels were determined by HomeDiagnostics, Inc. True Track smart system at intervals depicted in FIG.22. A drop in glucose level was seen as early as one-half hour aftertransdermal application followed by sustained depressed levels for up tofifteen hours. By twenty-four hours, glucose had returned topre-treatment levels followed by rebound ro hyperglycemic concentrationsfor the next twenty-four hours. Sustained release of transdermaladministered insulin has been demonstrated.

Pharmaceutical agents that may be delivered by this platform includeinsulins, GLP-1s, analgesics, anesthetics, narcotics, angiostaticsteroids, anti-inflammatory steroids, angiogenesis inhibitors,nonsteroidal anti-inflammatories, anti-infective agents, anti-fungals,anti-malarials, anti-tuberculosis agents, antivirals, alphaandrogenergic agonists, beta adrenergic blocking agents, carbonicanhydrase inhibitors, mast cell stabilizers, miotics, prostaglandins,antihistamines, antimicrotubule agents, antineoplastic agents,antiapoptotics, aldose reductase inhibitors, antihypertensives,antioxidants, growth hormone antagonists, vitrectomy agents adenosinereceptor antagonists, adenosine delaminate inhibitor, glycosylationantagonists, anti-aging peptides, topoisemerase inhibitors,anti-metabolites, alkylating agents, antiandrigens, anti-oestogens,oncogene activation inhibitors, telomerase inhibitors, antibodies orportions thereof, antisense oligonucleotides, fusion proteins,luteinizing hormone releasing hormones agonists, gonadotropin releasinghormone agonists, tyrosine kinase inhibitors, epidermal growth factorinhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2therapeutics, neurotensin antagonists, peripheral sigma ligands,endothelin ETA/receptor antagonists, antihyperglycemics, anti-glaucomaagents, anti-chromatin modifying enzymes, obesity management agents,anemia therapeutics, emesis therapeutics, neutropaenia therapeutics,tumor-induced hypercalcaemia therapeutics, blood anticoagulants,anti-proliferatives, immunosuppressive agents, tissue repair agents, andpsychotherapeutic agents.

Example 24 Formulation Effective in Treating Brain Tumors

The following example used a partial tumor resection brain tumor modelto investigate whether tissue injury resulted in an accelerated,proliferative index or accelerated tumor growth. It also indicated thatsuppression of inflammatory cytokines and vascular endothelial growthfactors with local sustained-release corticosteroid will alter the rateof recurrence and growth in an experimental mouse tumor model. Thisexperiment used a resection/recurrent mouse glioblatoma model inascertaining the effects of dexamethasone on the post-surgicalenvironment following tumor resection.

A pellet of 1.5 mg of 50/50 wt. dexamethasone/tocopheryl succinate wasprepared in a 1.0 diameter press. The in vitro kinetics are shown inFIG. 23.

Briefly, mice were anesthetized by intramuscular injection of a cocktailof ketamine (22-44 mg/kg), xylazine (2.5 mg/kg), and acepromazine (0.75mg/kg). Ten thousand GL-26 rat glioblastoma cells were implantedstereotactically into the right basal ganglia of the animal using amouse stereotactic frame (Kopf Instruments, Tujunga, Calif.). At day 15after tumor implantation, the animals were scanned in a 1.5T MRI with aT-1. Contrast medium was give via tail vein injection prior to scanning.At day 18 another imaging was done to confirm the tumor progression.Animals with similar tumor size were selected for the study. Animalsunderwent craniotomy and tumor resection on day 19 following generalanesthesia. The tumor was resected to about 80% completion. The extentof resection was verified by post-operative MRI imaging. Three animalseach with similar residual tumor were grouped into resected and resectedplus dexamethasone-tocopheryl succinate delivery system. In the treatedgroup sustained-release dexamethasone was placed into the resectioncavity. The expansion of the residual tumor was monitored by MR imaging.The growth rate was determined and compared to that of control andresection arms of the study.

Animals implanted with G126 mouse glioma cell line will grow to a meanvolume of 110 mm³ at day 25. The mean survival is 28 days. In thecurrent experiment there was a significant difference in the volume ofthe recurrent tumor at day 30 between the resected (122.5 mm³) and theresected group treated with intratumoral sustained-release dexamethasone(18 mm³) and the control (233.5 mm³). See FIG. 24. These data suggestthat dexamethasone delivered locally following resection appears to beeffective in altering the rate of recurrence.

Example 25 In Situ Personalized Anti-Cancer Vaccine Production

The use of aldehydes such as formaldehyde to kill or alter the cellularor viral components of pathogens for the formation of vaccines is wellknown. The Salk polio vaccine is one example. The pathogens are exposedto a carefully measured amount of an aqueous aldehyde solution resultingin the death of the pathogen or chemical alteration of the cellular orviral components to destroy pathogenisity. In many cases the resultantaltered cells, viruses, or components are recognized by the body'simmune system as foreign resulting in therapeutic antibody production.For the production of a patient-specific anticancer vaccine (PSAV) to atumor, because the highly reactive aqueous aldehyde solutions are verymobile fluids they would be difficult to confine to the target area ifinjected into the body; and considerable collateral damage to healthytissues might occur. Thus, presently the exposure of the targetmalignant cells to the aldehyde is done outside the body and theresultant attenuated pathogen material is then injected into the body.Excising tumor tissue for extracorporeal vaccine production can betraumatic, and often tumors such as glioblastomas are inoperable. Hence,there remains a need for an improved approach to PSAV techniques.

This embodiment allows for the precision injections of controlledamounts of novel aldehyde, especially formaldehyde, polyoxymethyleneprodrug formulations directly into tumors in the body. The precise,controlled nature of these prodrug injections limits cell death oraugmentation to tumor tissue only, with little or no collateral damageto healthy tissues. The subsequent release of resultant attenuated tumorcells or augmented cell material into the blood stream inducespersonalized antibody formation that eradicates any remaining originaltumor or daughter tumors that may have metathesized to other sites inthe body. This process is classified as producing a patient-specificanticancer vaccine (PSAV).

The novelty of this embodiment is the use of solid and liquidoxymethylene polymers as controlled release prodrugs of the desiredaldehydes. Aldehydes have the propensity to homopolymerize to a varietyof cyclic trimers and linear oxymethylene or substituted oxymethylenepolymers of a wide spectrum of molecular weights. In water, thesetrimers and polymers slowly revert back to their aldehyde monomers. Thisproperty offers the ability to inject with precision these aldehydeprodrugs or their injectable formulations with excipients into tumors inthe body to allow for the controlled and/or sustained release of thedesired aldehyde into the tumor with little or no damage to healthytissue. The subsequent release of killed or attenuated tumor cells orcellular material into the blood stream induces immune responses toproduce therapeutic antibodies to destroy tumor cells throughout thebody.

Some oxymethylene polymers and trimers for this embodiment are, forexample: Paraformaldehyde, Trioxane, Oxymethylene polymers ofacetaldehyde, Paraldehyde, and Oxymethylene polymers of gluteraldehyde.

These oxymethylene polymers and trimers can be implanted by themselvesor as mixtures with excipients into the tumor mass. A desirable,minimally invasive method is by injection through 20 gauge to 36 gaugehypodermic needles of fluid liquid polyoxymethylene/excipientformulations. Excipients are disclosed herein and in U.S. Pub. No.2006/0073182. Some example excipients useful in the present embodimentinclude benzyl benzoate, tocopherol acetate, and triethyl O-acetylcitrate. An illustrative but non-limiting example of a formulation wouldbe triethyl O-acetyl citrate containing 5 to 50% by weight of micronizedcrystals of paraformaldehyde.

Depending upon the size of the target tumor, 1.0 μl to 100 μl of thisformulation may be injected into the tumor mass.

Example 26 Omega-3 Fatty Acids and their Esters for Injectable SustainedDrug Release Formulations

As noted above, the embodiments thus provide for the novel concept ofinjections of omega-3 fatty acids and their esters by themselves or asnovel and therapeutic formulations with active agents directly intostrategic areas of the human or animal bodies to provide for thesustained release of the omega-3 compounds and therapeutic but nontoxiclevels of the active agents for periods of months to over a year.

The process of injecting small amounts of these omega-3 fatty acid/esteralone or their formulations containing active agents at the site of themalady is not only maximally effective and efficient but also avoids thewaste and potentially increased danger of systemic oral administration.These novel sustained drug release formulations of the omega-3 liquidsalone or in combination with the other excipients disclosed herein andin U.S. Pub. No. 2006/0073182 can be injected into a variety of bodyareas or organs such as but not limited to the breast, brain, pancreas,liver, prostate, lung, etc. An especially promising application isintraocular injection into the anterior or posterior segments of theeye. Among a number of maladies to be treated, as listed herein and inUS 2006/0073182, are those of the retina such as macular degeneration,retinitis pigmentosa, proliferative vitreoretinopathy, to name a few. Apotentially advantageous property of DHA, EPA, and their esters is theirimportance in maintaining healthy retinal tissue and their requiredpresence for proper development of neonatal retinal function. See, e.g.,Jeffrey et al., 36 (9) Lipids 859-71 (2001); SanGiovanni & Chew, 24 (1)Prog Retin Eye Res. 87-138 (2005); Bazan, 29 (5) Trends Neurosci. 263-71(2006); King et al., 26 (17) J. Neurosci. 4672-80 (2006). Indeed, it isquite possible these beneficial effects of DHA/EPA and their esters inneural development might lead to their injectable formulations beingpotent adjuvants for successful stem cell implantation and developmentespecially in the retina, brain, spinal cord, and the like. Also theseinjectable formulations use as adjuvants for successful stem celldevelopment of pancreatic tissue (diabetes), cardiac tissue (coronarytherapy), or skin tissue (burn therapy) to name a few awaitinvestigation.

Some more specific, but not limiting, examples contemplated forintraocular therapies are for inflammatory maladies of the retinal area.Injection through 25 G to 30 G needles into the posterior segment of 10μl to 60 μl liquid microspheres of ethyl DHA/ethyl EPA alone or asmixtures containing 10% to 50% by weight of microcrystallinedexamethasone or triamcinolone acetonide. This provides for themaintenance of therapeutic levels of the omega-3 fatty acids or theapproximately 0.1 to 1.0 μg/ml therapeutic concentration of the steroidsin the area of the retina for periods of months to over a year. In thecase of anti-VEGF therapy similar amounts of such agents as ranibizumabor bevacizumab could be employed in a similar manner with the omega-3excipients. The extensive list of other beneficial agents employed forthe list of a wide variety of maladies are disclosed herein and in U.S.Pub. No. 2006/0073182.

Example 27 Formulations Containing Steroids and Antioxidants

This embodiment relates generally to novel injectable and topicallyapplied formulations containing both steroids and antioxidants. Theseformulations allow the application of steroids to achieve their intendedbenefits (anti-inflammation, immune modulation) without initiation ofharmful oxidative chemistries. These example formulations are composedof one or more of the steroids listed in Group A combined with one ormore of the antioxidants listed in Group B and all dispersed ordissolved in one or more of the delivery vehicles selected from theexcipients described herein and listed in Group C and also described inU.S. Pat. Appl. Pub. No. 2006/0073182. Group A Steroids triamcinolonedexamethasone diethyl aminoacetate triamcinolone acetonide dexamethasoneisonicotinate triamcinolone diacetate dexamethasone palmitatetriamcinolone acetate prednisone triamcinolone disodium phosphateprednisolone triamcinolone hemisuccinate prednisolone acetatetriamcinolone benetonide prednisolone sodium phosphate dexamethasonemethylprednisolone dexamethasone acetate methylprednisolone acetatedexamethasone disodium methylprednisolone sodium succinate phosphatedexamethasone paramethasone 3,3-dimethylbutyrate cortisoneetrahydrocortexolone cortisone acetate betamethasone hydrocortisonebetamethasone acetate hydrocortisone acetate betamethasone disodiumphosphate tetrahydrocortisol betamethasone benzoate fludrocortisonebetamethasone valerate fludrocortisone acetate betamethasonedipropionate fludrocortisone phosphate betamethasone adamantoateanacortive beclomethasone anacortive acetate beclomethasone dipropionatemometasone furoate diflorasone fluocinolone diflorasone diacetate

Group B Antioxidants ascorbic acids and salts retinyl palmitate ascorbylpalmitate probucol ascorbyl dipalmitate erythorbic acid ascorbylstearate sodium erythorbate ascorbyl-2,6-dibutyrate α-lipoic acidd-tocopherol (α, β, γ, δ isomers) isocitrate dl-tocopherol (α, β, γ, δisomers) lutein/zeaxanthin/meso- zeaxanthin the acetate, hemisuccinate,nicotinate eugenol and succinate-PEG ester derivatives of isoeugenol theabove tocopherol isomers (−)-epicatechin glutathione(−)-epigallocatechin gallate β-carotine benzyl alcohol carnitine benzylbenzoate carnitine acetate 2,6-di-tertbutyl-4-methoxy phenol transreveratrol butylated hydroxytoluene retinoic acid butylatedhydroxyanisole retinyl palmitate quercetin melatonin catechin timololrutin luteolin coenzyme Q kaempferol fisetin thyroxine methyl gallatepyrroloquinolone superoxide dismutase

Group C Exipients d-tocopherol (α, β, γ, δ isomers) dimethyl sulfone(MSM) dl-tocopherol (α, β, γ, δ isomers) benzyl benzoate the acetate andesters of C-3 to liquid to semisolid poly-carbonate C-10 straight andbranched oligomers, such as those prepared by chain aliphatic acids withthe the polymerization of trimethylene above tocopherol isomerscarbonate or the ester exchange polymerization of diethylene carbonatewith aliphatic diols or polyoxyalkane diols [poly(di-1,2- propyleneglycol carbonate) or poly(tri-1,2-propylene glycol carbonate)] triethyl,tripropyl, or tribuyl esters tri-straight and branched chain C-1 to ofO-acetyl, O-propionyl, or C-10 aliphatic alcohol esters of O-butyrylcitrate citric acid omega-3 fatty acids and their ester propylene glycoldibenzoate with C-1 to C-10 straight and branched chain aliphaticalcohols dipropylene glycol dibenzoate tripropylene glycol dibenzoate

As mentioned above, to avoid harmful pro-oxidative chemistries careshould be taken not to expose the cells to too high a level of theantioxidants. This may present a problem as formulators develop aone-shot formulation that administers steroids and antioxidants formonths to a year or more. The formulation must incorporate enoughantioxidants to last this long without releasing pro-oxidativeconcentrations. This is achieved in this embodiment of the invention byusing lipophyllic prodrug forms of the antioxidants such as ascorbylpalmitate, tocopherol acetate, benzyl benzoate, and the like, whichslowly release the active, more hydrophyllic form into the cellularenvironment upon hydrolysis.

Examples of an injectable sustained release formulation of thisembodiment include formulations such as: (1) benzyl benzoate 60 pts/wtα-tocopherol acetate  5 pts/wt ascorbyl palmitate  5 pts/wttriamcinolone acetonate 40 pts/wt (2) α-tocopherol acetate 60 pts/wtascorbyl palmitate 10 pts/wt dexamethasone 40 pts/wt

Example 28 In vitro study of Dexamethasone in Triethyl O-Acetyl Citrate(TEAC)

To 760 mg of TEAC was added 240 mg of Dexamethasone with ample stirringto form a homogeneous mixture. Six mg (25 μl) and 12 mg (25 μl)microdrops of this mixture were each incubated in 10 ml of 0.9% salineat 37° C. Periodically, 8 ml portions were withdrawn for assaying andreplaced with 8 ml of fresh 0.9% saline. The release of Dex from aformulation consisting of 24% Dex in TEAC is depicted in FIG. 25. Therelease of Dex from a formulation consisting of a 6 mg (25 μl) microdropof 20% Dex in 1:1 TEAC/Tocopherol Acetate is reflected in FIG. 26. Insummary, these results indicate that adding Tocopherol Acetate to theTEAC excipient can extend the sustained release of therapeutic levels ofDex up to 450 days.

Example 29 In Vivo Study of Sustained Release of Active Agents from TEACFormulations

A microdrop of a mixture of 10% Dex in TEAC containing 200 μg of Dex wasinjected into the anterior chamber (AC) of the right eye of a rabbitwith a 30 G needle. Similarly, a microdrop of the mixture containing 400μg Dexamethasone was injected into the AC of the left eye of a rabbit.As illustrated in FIG. 27, the duration of therapeutic levels ofDexamethasone was seen to be twice as long in the left AC.

A 10% Dex in TEAC formulation was injected into a rabbit vitreouschamber/posterior segment (VC/PS). As shown in FIG. 28, sustainedtherapeutic intravitreal levels of Dex were maintained over sixty daysfollowing injection of 3 mg or 6 mg microdrops of a 10% Dex in TEACmixture into the VC/PS.

A portion of the formulation amounting to 80 μg of Dex was injected witha 30 gauge needle into the anterior chamber of a NZW rabbit and thekinetics measured by HPLC. Therapeutic levels were observed over atwelve-day period, as depicted in FIG. 29.

A portion of the of the formulation amounting to 900 μg of Dex wasadministered into the anterior chamber of a NZW rabbit with a 30 gaugeneedle and kinetics were measured by HPLC. Therapeutic levels wereobserved over an eighteen-day period, as illustrated in FIG. 30.

A microdrop of a mixture of 20% Ciprofloxacin free base (FB) in TEAC,containing 300 μg of Ciprofloxacin FB, was injected into the AC of arabbit eye. A therapeutic level of 2.44 μg/ml was maintained for up tofive days, as shown in FIG. 31.

Example 30 In Vivo Release of Cyclosporin from Formulations Placed inthe Eye

It has been reported (see, e.g., U.S. Pat. No. 5,294,604) thatperiocular administrations of cyclosporin A (CsA) are used to treatocular diseases involving serious intraocular inflammatory processesrequiring immunosuppression for sustained periods. Such diseases includeendogenous uveitis, Behcet's Disease, corneal transplantation, vernalkeratoconjunctivitis, ligneous keratoconjunctivitis, dry eye syndrome,anterior uveitis and onchocerciasis. The present embodiment provides forthe intraocular injections of CsA formulations with novel excipientsallowing for the sustained release of therapeutic, non-toxic levels ofCsA, useful as therapies for such diseases. This Example reveals thereduction to practice of the use of these novel CsA formulations.

Three (3.0) mg of a formulation containing a 40:60 mixture ofcyclosporin A (CsA) in tocopherol acetate was injected into the anteriorchamber of a 4.0-4.5 kg NZW rabbit. Aqueous humor samples were obtainedand assayed for CsA via liquid chromatography and mass spectrometry. Arelease profile is depicted in FIG. 32.

Approximately 14.0 mg of CsA (contained in a 25:75 mixture of CsA intriethyl acetyl citrate) was injected into the vitreous of a 4.0-4.5 kgNZW rabbit. Vitreous samples were obtained and assayed for CsA asdescribed above. A release profile is depicted in FIG. 33.

Example 31 Sustained Release and Stability of MonoclonalAntibody-Containing Formulations

Three formulations containing 0.25 mg monoclonal antibody (Mab) againstLSD were each injected into the vitreous cavity of 4 New Zealand Whiterabbits (ave. 4-4.5 kg). The first formulation the Mab was suspended inPBS buffer, the second and third containing lyophilized Mab in 25 μl ofeither Triethyl AcetylCitrate (TEAC) or Benzyl Benzoate (BB)respectively. Fifty (50) μl of vitreous were sampled from each animal asshown in Table 6 following intravitreal injections, and assayed for theMab LSD activity in the standard microtiter ELISA method (Biostride,Redwood City, Calif.). TABLE 6 Day Ave. Ab in PBS Ave. Ab in TEAC Ave.Ab in BB 1 3.5 1.4 3 71.5 7 49.5 3.6 1.2

The data, shown in FIG. 34, suggest that the half-life of the Mab in PBSis between three to five days: the Mab concentration on day three was71.5 μg/ml and day seven was 49.5 μg/ml. In contrast, the Mabconcentration released from the TEAC formulation on days one and sevenwere 3.5 μg/ml and 3.6 μg/ml, respectively. The Mab concentrationreleased from the BB formulation on days one and seven were 1.4 μg/mland 1.2 μg/ml, respectively. Comparable data interpretation on day sevensuggests that controlled sustained release of Mab in the rabbit vitreouscavity can be achieved with TEAC and BB. The controlled level was 13.7×(49.5/3.6) more effective in TEAC than in PBS alone, and 41.25×(49.5/1.2) more effective in BB than in PBS alone. Controlled-sustainedrelease of the Mab in TEAC and BB is apparent in this study, and thehalf-life of Mab in TEAC and BB could be well beyond seven days. Thespecificity of these assays suggests strongly that the integrity of theMab was not affected in the formulary with TEAC and BB. In conclusion,the formulations of the present invention provide for the sustainedrelease of sensitive polypeptides without denaturing their function.

Example 32 In Vivo Release of Rapamycin from TEAC Formulations

Five (5.0) mg rapamycin contained in a 10:90 rapamycin:TEAC mixture wereinjected into the vitreous cavity of one eye in three 4.0-4.5 kg. NZWrabbits. Vitreous sampling was performed in each animal, and theconcentration of released Rapamycin determined by liquid chromatographyand mass spectrometry. Results are depicted in FIG. 35, indicating thatthis formulation allowed the release of Rapamycin for over five months.

Example 33 Formulations for the In Vivo Release of Ketorolac Acid

Ketorolac acid and/or other nonsteroidal anti-inflammatory drugs(NSAIDs) are a different class of antiinflammatory drugs used widely inmedicine and in the eye. They are less potent than corticosteroids andhave fewer or less-severe side effects on the eye (such as glaucoma,cataracts which are common complications of corticosteroid use in theeye). Additionally, they may be used topically or in intraocularinjection with or without sustained release parameters. There are earlyclinical findings indicating that non-sustained-release use of NSAID canbe helpful in chronic macular edema. Hence, a sustained-releaseformulation may prove beneficial.

Eight-hundred (800) μg of ketorolac acid (♦) contained in a 20:80ketorolac acid:BB mixture and 700 μg of ketorolac acid (Δ) contained ina 20:80 ketorolac acid:TEAC mixture were injected into the anteriorchamber in one eye of each of two 4.0-4.5 kg NZW rabbits. Sampling ofthe aqueous humor for ketorolac determination by HPLC was performed, andthe results are shown in FIG. 36.

Five (5.0) mg (25 μl) of ketorolac acid (♦) contained in a 20:80ketorolac acid:BB mixture and 5 mg (25 μl) of ketorolac acid (▪)contained in 20:80 ketorolac acid:TEAC mixture were injected into thevitreous cavity in one eye each of two 4.0-4.5 kg NZW rabbits. Samplingof the vitreous humor for ketorolac acid concentration was performed,and the results of the determination by HPLC are shown in FIG. 37.

Modifications of the above described modes for carrying out theinvention that are obvious to those of ordinary skill in the surgical,pharmaceutical, or related arts are intended to be within the scope ofthe appended claims

1. A pharmaceutical formulation for the sustained release of an activeagent consisting essentially of a biocompatible, biodegradable,non-polymeric excipient and an active agent or pharmaceuticallyacceptable salt thereof, wherein said formulation is capable of beingimplanted by injection.
 2. A pharmaceutical formulation for implantationinto a patient for the sustained release of an active agent consistingessentially of a biocompatible, biodegradable, non-polymeric excipientand an active agent or pharmaceutically acceptable salt thereof, whereinsaid formulation exhibits an in vitro or in vivo dissolution profilewherein about 2% to about 100% of the active agent is released over aperiod ranging from about 1 day to about 105 days.
 3. A pharmaceuticalformulation for implantation into a patient for the sustained release ofan active agent comprising a biocompatible, biodegradable, non-polymericexcipient and an active agent or pharmaceutically acceptable saltthereof, wherein said formulation exhibits an in vitro or in vivodissolution profile wherein about 2% to about 100% of the active agentis released over a period ranging from about 1 day to about 365 days. 4.The pharmaceutical formulation of claim 1, wherein about 2% to about 60%of the active agent is released over a period ranging from about 1 dayto at least about 365 days.
 5. The pharmaceutical formulation of claim1, comprising an active agent at a concentration from about 5% to about50% of the implant and biodegradable, biocompatible excipient at aconcentration of at least about 5% of the implant.
 6. The pharmaceuticalformulation of claim 1, comprising an active agent at a concentrationfrom about 0.5% to about 95% of the implant and the correspondingconcentration of the excipient ranges from about 5% to about 99.5%. 7.The pharmaceutical formulation of claim 1, wherein said biocompatible,biodegradable excipient is selected from the group consisting of benzylbenzoate; esters of benzoic acid with straight, branched, or cyclicchain aliphatic alcohols having one to twenty carbon atoms wherein oneof the hydrogen atoms on the aliphatic chain is replaced with a hydroxylgroup (e.g., such alcohols as methanol, ethanol, n-propanol, i-propanol,n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol,neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol,n-decanol, and the like); d, 1 and d1 isomers of α, β, δ, ε, ηtocopherols and similar isomers of the tocotrienols and the esters ofthese tocopherols and tocotrienols with: straight and branched chain C₂to C₂₀ aliphatic acids, or their esters of C₃ to C₂₀ straight chaindicarboxylic acids, including maleic, malic, fumaric, succinic, or theiresters with lactic, glycolic, benzoic, nicotinic, pyruvic acids,succinic-PEG ester; the mono, di, and tri esters of O-acetylcitric acidor O-propionylcitric acid or O-butyrylcitric acid with C₁ to C₁₀straight and branched chain aliphatic alcohols; the mono, di, and triesters of citric acid with C₁ to C₁₀ straight and branched chainaliphatic alcohols; dibenzoate esters of poly(oxyethylene) diols havinglow water solubility; poly(oxypropylene)diols having low watersolubility; liquid and semisolid polycarbonate oligomers, and dimethylsulfone.
 8. The pharmaceutical formulation of claim 1, wherein saidactive agent is selected from the group consisting of analgesics,anesthetics, narcotics, angiostatic steroids, anti-inflammatorysteroids, angiogenesis inhibitors, nonsteroidal anti-inflammatories,anti-infective agents, anti-fungals, anti-malarials, anti-tuberculosisagents, antivirals, alpha androgenergic agonists, beta adrenergicblocking agents, carbonic anhydrase inhibitors, mast cell stabilizers,miotics, prostaglandins, antihistamines, antimicrotubule agents,antineoplastic agents, antipoptotics, aldose reductase inhibitors,antihypertensives, antioxidants, growth hormone antagonists, vitrectomyagents, adenosine receptor antagonists, adenosine deaminase inhibitor,glycosylation antagonists, anti aging peptides, topoisemeraseinhibitors, anti-metabolites, alkylating agents, antiandrigens,anti-oestogens, oncogene activation inhibitors, telomerase inhibitors,antibodies or portions thereof, antisense oligonucleotides, fusionproteins, luteinizing hormone releasing hormones agonists, gonadotropinreleasing hormone agonists, tyrosine kinase inhibitors, epidermal growthfactor inhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2therapeutics, neurotensin antagonists, peripheral sigma ligands,endothelin ETA/receptor antagonists, antihyperglycemics, anti-glaucomaagents, anti-chromatin modifying enzymes, obesity management agents,anemia therapeutics, emesis therapeutics, neutropaenia therapeutics,tumor-induced hypercalcaemia therapeutics, blood anticoagulants,immunosuppressive agents, tissue repair agents, insulins,glucagon-like-peptides, botulinum toxins, and psychotherapeutic agents.9. A method for treating joint inflammation comprising the step of:implanting, by injection, a pharmaceutical formulation comprising abiodegradable, biocompatible, nonpolymeric excipient and a steroidal ornon-steroidal anti-inflammatory into a strategic position in theinflamed joint to provide controlled and sustained release of atherapeutically effective but nontoxic level of the anti-inflammatory tothe affected areas.
 10. The method of claim 9 wherein saidpharmaceutical formulation further comprises an antioxidant.
 11. Thepharmaceutical formulation of claim 8, wherein the active agent is oneor more steroidal anti-inflammatory agents selected from the groupconsisting of 21-acetoxypregnenolone, alclometasone, algestone,amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,clobetasol, clobetasone, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, dexamethasone 21-acetate, dexamethasone 21-phosphatedi-Na salt, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide.
 12. The pharmaceutical formulation of claim 11, whereinthe active agent is one or more steroidal anti-inflammatory agentsselected from the group consisting of cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone acetonide.
 13. The pharmaceutical formulation of claim 12,wherein the active agent is one or more steroidal anti-inflammatoryagents selected from the group consisting of dexamethasone andtriamcinolone acetonide.
 14. The pharmaceutical formulation of claim 8,wherein the active agent is one or more non-steroidal anti-inflammatoryagents selected from the group consisting of naproxin; diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; ibuprofen; ketoprofen; r-flurbiprofen; mefenamic; nabumetone;tolmetin, and sodium salts of each of the foregoing; ketorolacbromethamine; ketorolac tromethamine; ketorolac acid; choline magnesiumtrisalicylate; rofecoxib; valdecoxib; lumiracoxib; etoricoxib; aspirin;salicylic acid and its sodium salt; salicylate esters of alpha, beta,gamma-tocopherols and tocotrienols (and all their d, 1, and racemicisomers); methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl,esters of acetylsalicylic acid; tenoxicam; aceclofenac; nimesulide;nepafenac; amfenac; bromfenac; flufenamate; and phenylbutazone.
 15. Thepharmaceutical formulation of claim 8, wherein the active agent is oneor more anti-infectives selected from the group consisting of2,4-diaminopyrimidines, nitrofurans, quinolones and quinolone analogs,sulfonamides, sulfones, clofoctol, hexedine, methenamine, methenamineanhydromethylene-citrate, methenamine hippurate, methenamine mandelate,methenamine sulfosalicylate, nitroxoline, taurolidine, xibomol,moxifloxacin, and vancomycin.
 16. A method of treating inflammatoryconditions comprising delivering to a patient in need thereof thepharmaceutical formulation of claim
 12. 17. The method of claim 16,wherein said pharmaceutical formulation further comprises a quinolone orquinalone analog antibiotic.
 18. The method of claim 17, wherein saidpharmaceutical formulation further comprises an antioxidant.
 19. Amethod of treating a malady of the eye by implanting the pharmaceuticalformulation of claim 1, wherein said malady is selected from the groupconsisting of allergic and infectious conjunctivitis, uveitis of theanterior and posterior segments, infectious endophthalmitis of theanterior segment and posterior segment, dry-eye syndrome, post-surgicalinflammation and infection of the anterior and posterior segments,angle-closure glaucoma, open-angle glaucoma, post-surgical glaucomaprocedures, exopthalmos, scleritis, episcleritis, Grave's disease,pseudotumor of the orbit, lymphoma of the orbit, tumors of the orbit,orbital cellulitis, blepharitis, intraocular tumors, retinoblastoma,malignant melanoma, retinal fibrosis, vitreous substitute and vitreousreplacement, iris neovascularization from cataract surgery, macularedema in central retinal vein occlusion, cellular transplantation (as inretinal pigment cell transplantation), cystiod macular edema,psaudophakic cystoid macular edema, diabetic macular edema,pre-phthisical ocular hypotomy, proliferative vitreoretinopathy,proliferative diabetic retinopathy, exudative age-related maculardegeneration, extensive exudative retinal detachment (Coat's disease),diabetic retinal edema, diffuse diabetic macular edema, ischemicopthalmopathy, chronic focal immunologic and chemical corneal graftreaction, neovascular glaucoma, pars plana vitrectomy (for proliferativediabetic retinopathy), pars plana vitrectomy for proliferativevitreoretinopathy, sympathetic ophthalmia, intermediate uveitis, chronicuveitis, intraocular infection such as endophthalmitis, and Irvine-Gasssyndrome; conditions of inflammatory and immunological in nature,sequalae of surgical complications, and acquired and hereditary ocularconditions such as Tay-Sach's disease, Niemann-Pick's disease,cystinosis, corneal dystrophies and multiple myeloma.
 20. Thepharmaceutical formulation of claim 2, wherein said formulation is asolid form containing from 1% to about 60% of a limited solubility,biocompatible, biodegradable nonpolymeric excipient.
 21. Thepharmaceutical formulation of claim 2, wherein said formulation is a gelform containing from 20% to about 80% of a limited solubility,biocompatible, biodegradable nonpolymeric excipient.
 22. Thepharmaceutical formulation of claim 2, wherein said formulation is aninjectable liquid or gel form containing from 30% to about 99.9% of alimited solubility, biocompatible, biodegradable nonpolymeric excipient.23. A pharmaceutical formulation for the sustained release of an activeagent consisting essentially of a biocompatible, biodegradable,nonpolymeric excipient and an active agent or pharmaceuticallyacceptable salt thereof, wherein said formulation is capable of beingimplanted by injection, and wherein said biocompatible, biodegradableexcipient is selected from the group consisting of tocopherol isomersand tocotrienol isomers and their esters; benzyl benzoate; esters ofbenzoic acid with straight, branched, or cyclic chain aliphatic alcoholshaving one to twenty carbon atoms wherein one of the hydrogen atoms onthe aliphatic chain is replaced with a hydroxyl group; dibenzoate estersof poly(oxyethylene) diols having low water solubility; dimethyl sulfonepoly(oxypropylene) diols having low water solubility; the mono, di, andtriesters of O-acetylcitric acid with C₁ to C₁₀ straight and branchedchain aliphatic alcohols; mono, di, and triesters of citric acid with C₁to C₁₀ straight and branched chain aliphatic alcohols; dimethyl sulfone;omega-3 fatty acids and their esters of C₁ to C₈ straight and branchedchain aliphatic alcohols; and liquid and semisolid polycarbonateoligomers.
 24. The pharmaceutical formulation of claim 7, wherein saidliquid to semisolid polycarbonate oligomers is selected from the groupconsisting of those polycarbonate oligomers prepared by thepolymerization of trimethylene carbonate [poly(1,3-propanediolcarbonate)], the ester exchange polymerization of diethylene carbonatewith aliphatic diols or polyoxyalkane diols [poly(di-1,2-propyleneglycol carbonate), and poly(tri-1,2-propylene glycol carbonate)].
 25. Aliquid, solid or gel formulation conveniently implantable in a braintumor for the sustained release of active agents, comprising one or moreof the excipients selected from group (a) and one or more of thepharmaceutical agents selected from group (b) or group (c), or bothgroup (b) and group (c): (a) benzyl benzoate; esters of benzoic acidwith straight, branched, or cyclic chain aliphatic alcohols having oneto twenty carbon atoms wherein one of the hydrogen atoms on thealiphatic chain is replaced with a hydroxyl group (e.g., such alcoholsas methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,s-butanol, t-butanol, n-pentanol, i-pentanol, neo-pentanol, n-hexanol,cyclohexanol, n-heptanol, n-octonol, n-nonanol, n-decanol, and thelike), d.1 and d1 isomers of α, β, δ, ε, η tocopherols and similarisomers of the tocotrienols and the esters of these tocopherols andtocotrienols with straight and branched chain C₁ to C₁₀ aliphatic acids,C₃ to C₂₀ straight chain dicarboxylic acids, maleic, malic, fumaric,lactic, glycolic, benzoic, nicotinic, pyruvic acids, succinic-PEG ester,the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitricacid or O-butyrylcitric acid with C₁ to C₁₀ straight and branched chainaliphatic alcohols; the mono, di, and tri esters of citric acid with C₁to C₁₀ straight and branched chain aliphatic alcohols, dibenzoate estersof poly(oxyethylene) diols having low water solubility,poly(oxypropylene)diols having low water solubility, liquid andsemisolid polycarbonate oligomers, and dimethyl sulfone, diethyleneglycol dibenzoate, triethylene glycol dibenzoate, dibenzoate esters ofpoly(oxyethylene) diols of up to about 400 mwt, propylene glycoldibenzoate, dipropylene glycol dibenzoate, tripropylene glycoldibenzoate, dibenzoate esters of poly(oxypropylene) diols of up to about3000 mwt; poly(oxypropylene) diols of up to about 3000 mwt, dimethylsulfone, liquid to semisolid polycarbonate oligomers, polymers andcopolymers of glycolic and lactic acids, poly(lactic acid) andpoly(glycolic acid); (b) tetrahydrocortisol;4,9(11)-pregnadien-17α,21-diol-3,20-dione;4,9(11)-pregnadien-17α,21-diol-3,20-dione-21-acetate; 11-epicortisol;17α-hydroxyprogesterone; tetrahydrocortexolone; cortisone; cortisoneacetate; hydrocortisone; hydrocortisone acetate; fludrocortisones;fludrocortisone acetate; fludrocortisone phosphate; prednisone;prednisolone; prednisolone sodium phosphate; methylprednisolone,methylprednisolone acetate; methylprednisolone sodium succinate;triamcinolone; triamcinolone-16,21-diacetate; triamcinolone acetonide;triamcinolone acetonide-21-acetate; triamcinolone acetonide-21-disodiumphosphate; triamcinolone acetonide-21-hemisuccinate; triamcinolonebenetonide; triamcinolone hexacetonide; fluocinolone; fluocinoloneacetate; fluocinolone acetonide; dexamethasone;dexamethasone-21-acetate; dexamethasone-21-(3,3-dimethylbutyrate);dexamethasone-21-phosphate disodium salt;dexamethasone-21-diethylaminoacetate; dexamethasone-21-isonicotinate;dexamethasone-21-dipropionate; dexamethasone-21-palmitate;betamethasone; betamethasone-21-acetate; betamethasone-21-adamantoate;betamethasone-17-benzoate; betamethasone-17,21-dipropionate;betamethasone-17-valerate; betamethasone-21-phosphate disodium salt;beclomethasone; beclomethasone dipropionate; diflorasone; diflorasonediacetate; mometasone furoate; acetazolamide; naproxen; naproxin sodiumsalt; diclofenac; diclofenac sodium salt; celecoxib; rofecoxib;valdecoxib; etoricocib; lumiracoxib; sulindac; sulindac sodium salt;diflunisal; diflunisal sodium salt; piroxicam; indomethacin;indomethacin sodium salt; etodolac; etodolac sodium salt; meloxicam;ibuprofen; ibuprofen sodium salt; ketoprofen; ketoprofen sodium salt;r-flurbiprofen; mefenamic; mefenamic sodium salt; nabumetone; tolmetin;tolmetin sodium salt; ketorolac bromethamine; ketorolac tromethamine;ketorolac acid; choline magnesium trisalicylate; aspirin; salicylicacid; salicylic acid sodium salt; salicylate esters of alpha, beta,gamma-tocopherols (and all their d, 1, and racimic isomers); tenoxicam;aceclofenac; nimesulide; nepafenac; amfenac; bromfenac; flufenamate;phenylbutazone; CV 247; pegaptanib octasodium; ranibizumab;2-methoxyestradiol; shark cartilage extract; NX-278-L ant-VEGF aptamer;squalamine; 2′-O-methoxyethyl) antisense C-raf oncogene inhibitor;vitronectin and osteopontin antagonist; combretstatin A-4 phosphate; Fabfragment alpha-V/beta-1 integrin antagonist; alpha-v/beta-3 integrinantagonist; matrix metalloprotienase inhibitor; matrix metalloprotienaseinhibitor; urokinase plasminogen activator fragment; vascularendothelial growth factor antagonist; kdr tyrosine kinase inhibitor;cytochalasin E; kallikrinin-binding protein; combretastatin analog;pigment-epithelium derived growth factor; pigment-epithelium derivedgrowth factor; plasminogen kringle; rapamycin; cytokine synthesisinhibitor/p38 mitogen-activated protein kinaseinhibitor; vascularendothelial growth factor antagonist; vascular endothelial growth factorantagonist; vascular endothelial growth factor antagonist; vascularendothelial growth factor antagonist; FGF1 receptor antagonist/tyrosinekinase inhibitor (Pfizer/Sugen); endostatin, vascular endothelial growthfactor antagonist; bradykinin B1 receptor antagonist;bactericidal/permeability-increasing protein; protein kinase Cinhibitor; ruboxistaurinn mesylate; polysulphonic acid derivatives;growth factor antagonists; Tunica internal endothelial cell kinase;acetylcysteine; mannitol; antineoplaston; human corticotropin-releasingfactor; VN40101M; everolimus; GW572016; thalidomide; temozolomide;tariquidar; doxorubicin; dalteparin; tarceva; CC-5013; hCRF;bevacizumab; melphalan; thiotepa; depsipeptide; erlotinib; tamoxifen;bortezomib; lenalidomide; vorinostat; temsirolimus; modifinil;enzastuarin; motexafin gadolinium; F-18-OMFD-PET; pemetrexed disodium;ZD6474; valproic acid; vincristine; irinotecan; PEG-interferon alpha-2b;procarbazine; lonafarnib; arsenic trioxide; GP9; carboplatin;cyclophosphamide; 1311-TM-601; lapatinib; O6-benzylguanine; TP-38 toxin;cilengitide; poly-ICLC; FR901228; TransMid™; talabostat; ixabepilone;AEE788; sirolimus; alanosine; sorafenib; efaproxiral; carmustine;¹³¹Iodine monoclonal antibody TNT-1/B; intratumoral TransMid™;topatecan; lomustine; ³²Phosphorus; 18F-fluorodeoxyglucose; vinblastine;BMS-247550; CC-8490; IL 13-PE38QQR; imatib mesylate; hydroxyurea; G207;radiolabeled monoclonal antibody; 2-deoxyglucose; talampanel; retinoicacid; gefitinib; tipifarnib; CPT-11; rituximab; efaproxiral; PS-341;capecitabine; G-CFS; vinorelbine; DCVax®-Brain; paclitaxel; patipilone;iressa; methotrexate; ABT-751; oxaliplatin; MS-275; trastuzumab;pertuzumab; PS-341; 17AAG; lenalidomide; campath-1H; somatostatinanalog; resveratrol; CEP-7055; CEP-5214; PTC-299; inhibitors ofhepatocyte growth factor; statins; receptor tyrosine kinase inhibitors;aspirin (acetylsalicylic acid), and peroxisome proliferator-activatedreceptor (PPAR-alpha) activators (fenofibrate and clofibrate); (c)Anti-neovascularization steroids selected from the group consisting of:21-nor-5β-pregnan-3α,17α,20-triol-3-acetate;21-nor-5α-pregnan-3α,17α,20-triol-3-phosphate;21-nor-5β-pregn-17(20)en-3α,16-diol; 21-nor-5β-pregnan-3α,17β,20-triol;20-acetamide-21-nor-5β-pregnan-3α,17α-diol-3-acetate; 3βacetamido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate;21-nor-5α-pregnan-3α,17β,20-triol;21α-methyl-5β-pregnan-3α,11β,17α,21-tetrol-20-one-21-methyl ether;20-azido-21-nor-5β-pregnan-3α,17α-diol;20(carbethoxymethyl)thio-21-nor-5β-pregnan-3α,17α-diol;20-(4-fluorophenyl)thio-21-nor-5β-pregnan-3α,17α-diol;16α-(2-hydroxyethyl)-17β-methyl-5β-androstan-3α,17α diol;20-cyano-21-nor-5β-pregnan-3α,17α-diol;17α-methyl-5β-androstan-3α,17β-diol; 21-nor-5β-pregn-17(20)en-3α-ol;21-or -5β-pregn-17(20)en-3α-ol-3-acetate;21-nor-5-pregn-17(20)-en-3α-ol-16-acetic acid 3-acetate;3β-azido-5β-pregnan-11β,17α,21-triol-20-one-21-acetate; and5β-pregnan-11β,17α,21-triol-20-one; 4-androsten-3-one-17β-carboxylicacid; 17α-ethynyl-5(10)-estren-17β-ol-3-one; and17α-ethynyl-1,3,5(10)-estratrien-3,17β-diol.
 26. The formulation ofclaim 25, wherein said liquid to semisolid polycarbonate oligomers isselected from the group consisting of those polycarbonate oligomersprepared by the polymerization of trimethylene carbonate[poly(1,3-propanediol carbonate)], the ester exchange polymerization ofdiethylene carbonate with aliphatic diols or polyoxyalkane diols[poly(di-1,2-propylene glycol carbonate), and poly(tri-1,2-propyleneglycol carbonate)].
 27. The formulation of claim 25, wherein said statinis selected from the group consisting of atorvastatin, fluvastatin,rosuvastatin, pravastatin, simvastatin, lovastatin, and cerivastatin.28. The pharmaceutical formulation of claim 1, wherein said active agentis an oxymethylene polymer or trimer.
 29. The pharmaceutical formulationof claim 28, wherein said oxymethylene polymer or trimer is selectedfrom the group consisting of Paraformaldehyde, Trioxane, Oxymethylenepolymers of acetaldehyde, Paraldehyde, and Oxymethylene polymers ofgluteraldehyde.
 30. The pharmaceutical formulation of claim 8, whereinsaid antioxidant is selected from the group consisting of ascorbic acidsand salts, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl stearate,ascorbyl-2,6-dibutyrate, d-tocopherol (α, β, γ, δ isomers),d1-tocopherol (α, β, γ, δ isomers), the acetate, hemisuccinate,nicotinate and succinate-PEG ester derivatives of the above tocopherolisomers, glutathione, β-carotine, carnitine, carnitine acetate, transreveratrol, retinoic acid, retinyl palmitate, melatonin, timolol,luteolin, kaempferol, thyroxine, pyrroloquinolone, retinyl palmitate,probucol, erythorbic acid, sodium erythorbate, α-lipoic acid,isocitrate, lutein/zeaxanthin/meso-zeaxanthin, eugenol, isoeugenol,(−)-epicatechin, (−)-epigallocatechin gallate, benzyl alcohol, benzylbenzoate, 2,6-di-tertbutyl-4-methoxy phenol, butylated hydroxytoluene,butylated hydroxyanisole, quercetin, catechin, rutin, coenzyme Q,fisetin, methyl gallate, and superoxide dismutase.
 31. Thepharmaceutical formulation of claim 30, further comprising a steroid orquinolone anti-infective.
 32. The pharmaceutical formulation of claim31, wherein said quinolone anti-infective is selected from the groupconsisting of cinoxacin, ciprofloxacin, clinafloxacin, difloxacin,enoxacin, fleroxacin, flumequine, gatifloxacin, grepafloxacin,lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin,ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid,piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin,tosufloxacin, and trovafloxacin.
 33. The pharmaceutical formulation ofclaim 31, wherein said steroid is selected from the group consisting oftriamcinolone, triamcinolone acetonide, triamcinolone diacetate,triamcinolone acetate, triamcinolone disodium phosphate, triamcinolonehemisuccinate, triamcinolone benetonide, dexamethasone, dexamethasoneacetate, dexamethasone disodium phosphate, dexamethasone3,3-dimethylbutyrate, cortisone, cortisone acetate, hydrocortisone,hydrocortisone acetate, tetrahydrocortisol, fludrocortisones,fludrocortisone acetate, fludrocortisone phosphate, anacortive,anacortive acetate, mometasone furoate, fluocinolone, dexamethasonediethyl aminoacetate, dexamethasone isonicotinate, dexamethasonepalmitate, prednisone, prednisolone, prednisolone acetate, prednisolonesodium phosphate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, paramethasone,etrahydrocortexolone, betamethasone, betamethasone acetate,betamethasone disodium phosphate, betamethasone benzoate, betamethasonevalerate, betamethasone dipropionate, betamethasone adamantoate,beclomethasone, beclomethasone dipropionate, diflorasone, anddiflorasone diacetate.
 34. The pharmaceutical formulation of claim 1,wherein said excipient or active agent is an omega-3 fatty acid or anester thereof.